Abstract
The proteasome is involved in the regulation of all cellular pathways and consequently plays a central role in the control of cellular homeostasis. Together with its regulators, it is at the frontline, both as an actor and as a target, in human health and when homeostasis is disturbed in disease. In this review, we aim to provide an overview of the many levels at which the functions of the proteasome and its regulators can be regulated to cope with cellular needs or are altered in pathological conditions.
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References
Navon A, Ciechanover A (2009) The 26 S proteasome: from basic mechanisms to drug targeting. J Biol Chem 284:33713–33718
Meiners S, Keller IE, Semren N, Caniard A (2014) Regulation of the proteasome: evaluating the lung proteasome as a new therapeutic target. Antioxid Redox Signal 21:2364–2382
Deshaies RJ (2014) Proteotoxic crisis, the ubiquitin-proteasome system, and cancer therapy. BMC Biol 12:94
Manasanch EE, Orlowski RZ (2017) Proteasome inhibitors in cancer therapy. Nat Rev Clin Oncol 14:417–433
Njomen E, Tepe JJ (2019) Proteasome activation as a new therapeutic approach to target proteotoxic disorders. J Med Chem 62:6469–6481
Huang X, Dixit VM (2016) Drugging the undruggables: exploring the ubiquitin system for drug development. Cell Res 26:484–498
Lai AC, Crews CM (2017) Induced protein degradation: an emerging drug discovery paradigm. Nat Rev Drug Discov 16:101–114
Dantuma NP, Lindsten K, Glas R, Jellne M, Masucci MG (2000) Short-lived green fluorescent proteins for quantifying ubiquitin/proteasome-dependent proteolysis in living cells. Nat Biotechnol 18:538–543
Fuchs ACD, Hartmann MD (2019) On the origins of symmetry and modularity in the proteasome family: symmetry transitions are pivotal in the evolution and functional diversification of self-compartmentalizing proteases. BioEssays 41:e1800237
Coux O, Nothwang HG, Silva Pereira I, Recillas Targa F, Bey F, Scherrer K (1994) Phylogenic relationships of the amino acid sequences of prosome (proteasome, MCP) subunits. Mol Gen Genet MGG 245:769–780
Groll M, Ditzel L, Löwe J, Stock D, Bochtler M, Bartunik HD, Huber R (1997) Structure of 20S proteasome from yeast at 2.4 A resolution. Nature 386:463–471
Silva Pereira I, Bey F, Coux O, Scherrer K (1992) Two mRNAs exist for the Hs PROS-30 gene encoding a component of human prosomes. Gene 120:235–242
Yang Y, Waters JB, Früh K, Peterson PA (1992) Proteasomes are regulated by interferon gamma: implications for antigen processing. Proc Natl Acad Sci USA 89:4928–4932
Sijts EJAM, Kloetzel PM (2011) The role of the proteasome in the generation of MHC class I ligands and immune responses. Cell Mol Life Sci 68:1491–1502
Guillaume B, Chapiro J, Stroobant V, Colau D, Van Holle B et al (2010) Two abundant proteasome subtypes that uniquely process some antigens presented by HLA class I molecules. Proc Natl Acad Sci USA 107:18599–18604
Fabre B, Lambour T, Garrigues L, Ducoux-Petit M, Amalric F et al (2014) Label-free quantitative proteomics reveals the dynamics of proteasome complexes composition and stoichiometry in a wide range of human cell lines. J Proteome Res 13:3027–3037
Murata S, Sasaki K, Kishimoto T, Niwa SISI, Hayashi H, Takahama Y, Tanaka K (2007) Regulation of CD8+ T cell development by thymus-specific proteasomes. Science 316:1349–1353
Murata S, Takahama Y, Kasahara M, Tanaka K (2018) The immunoproteasome and thymoproteasome: functions, evolution and human disease. Nat Immunol 19:923–931
Qian MX, Pang Y, Liu CH, Haratake K, Du BY et al (2013) Acetylation-mediated proteasomal degradation of core histones during DNA repair and spermatogenesis. Cell 153:1012–1024
Padmanabhan A, Vuong SAT, Hochstrasser M (2016) Assembly of an evolutionarily conserved alternative proteasome isoform in human cells. Cell Rep 14:2962–2974
Hammack LJ, Kusmierczyk AR (2016) Assembly of proteasome subunits into non-canonical complexes in vivo. Biochem Biophys Res Commun 482:6–11
Fabre B, Lambour T, Garrigues L, Amalric F, Vigneron N et al (2015) Deciphering preferential interactions within supramolecular protein complexes: the proteasome case. Mol Syst Biol 11:1–16
Wójcik C, DeMartino GN (2002) Analysis of Drosophila 26 S proteasome using RNA interference. J Biol Chem 277:6188–6197
Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Fanourakis G et al (2002) Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci USA 99:14374–14379
Meiners S, Heyken D, Weller A, Ludwig A, Stangl K et al (2003) Inhibition of proteasome activity induces concerted expression of proteasome genes and de novo formation of mammalian proteasomes. J Biol Chem 278:21517–21525
Koizumi S, Hamazaki J, Murata S (2018) Transcriptional regulation of the 26S proteasome by Nrf1. Proc Jpn Acad Ser B Phys Biol Sci 94:325–336
Radhakrishnan SK, Lee CS, Young P, Beskow A, Chan JY, Deshaies RJ (2010) Transcription factor Nrf1 mediates the proteasome recovery pathway after proteasome inhibition in mammalian cells. Mol Cell 38:17–28
Steffen J, Seeger M, Koch A, Krüger E, Kruger E (2010) Proteasomal degradation is transcriptionally controlled by TCF11 via an ERAD-dependent feedback loop. Mol Cell 40:147–158
Dikic I (2017) Proteasomal and autophagy degradation systems. Annu Rev Biochem 86:193–224
Gaczynska M, Goldberg AL, Tanaka K, Hendil KB, Rock KL (1996) Proteasome subunits X and Y alter peptidase activities in opposite ways to the interferon-gamma-induced subunits LMP2 and LMP7. J Biol Chem 271:17275–17280
Chondrogianni N, Tzavelas C, Pemberton AJ, Nezis IP, Rivett AJ, Gonos ES (2005) Overexpression of proteasome beta5 assembled subunit increases the amount of proteasome and confers ameliorated response to oxidative stress and higher survival rates. J Biol Chem 280:11840–11850
Li D, Dong Q, Tao Q, Gu J, Cui Y et al (2015) c-Abl regulates proteasome abundance by controlling the ubiquitin-proteasomal degradation of PSMA7 subunit. Cell Rep 10:484–497
Hu XT, Chen W, Wang D, Shi QL, Zhang FB et al (2008) The proteasome subunit PSMA7 located on the 20q13 amplicon is overexpressed and associated with liver metastasis in colorectal cancer. Oncol Rep 19:441–446
Sahara K, Kogleck L, Yashiroda H, Murata S (2014) The mechanism for molecular assembly of the proteasome. Adv Biol Regul 54:51–58
Chondrogianni N, Gonos ES (2007) Overexpression of hUMP1/POMP proteasome accessory protein enhances proteasome-mediated antioxidant defence. Exp Gerontol 42:899–903
Shin SW, Shimizu N, Tokoro M, Nishikawa S, Hatanaka Y et al (2013) Mouse zygote-specific proteasome assembly chaperone important for maternal-to-zygotic transition. Biol Open 2:170–182
Bai M, Zhao X, Sahara K, Ohte Y, Hirano Y et al (2014) Assembly mechanisms of specialized core particles of the proteasome. Biomolecules 4:662–677
Le Tallec B, Barrault MB, Courbeyrette R, Guérois R, Marsolier-Kergoat MC, Peyroche A (2007) 20S proteasome assembly is orchestrated by two distinct pairs of chaperones in yeast and in mammals. Mol Cell 27:660–674
Fricke B, Heink S, Steffen J, Kloetzel PM, Krüger E (2007) The proteasome maturation protein POMP facilitates major steps of 20S proteasome formation at the endoplasmic reticulum. EMBO Rep 8:1170–1175
Hegde RS, Keenan RJ (2011) Tail-anchored membrane protein insertion into the endoplasmic reticulum. Nat Rev Mol Cell Biol 12:787–798
Akahane T, Sahara K, Yashiroda H, Tanaka K, Murata S (2013) Involvement of Bag6 and the TRC pathway in proteasome assembly. Nat Commun 4:2234
Hendil KB (1988) The 19 S multicatalytic ‘prosome’ proteinase is a constitutive enzyme in HeLa cells. Biochem Int 17:471–477
Cuervo AM, Palmer A, Rivett AJ, Knecht E (1995) Degradation of proteasomes by lysosomes in rat liver. Eur J Biochem 227:792–800
Tanaka K, Ichihara A (1989) Half-life of proteasomes (multiprotease complexes) in rat liver. Biochem Biophys Res Commun 159:1309–1315
Marshall RS, Li F, Gemperline DC, Book AJ, Vierstra RD (2015) Autophagic degradation of the 26S proteasome is mediated by the dual ATG8/ubiquitin receptor RPN10 in Arabidopsis. Mol Cell 58:1053–1066
Waite KA, De-La Mota-Peynado A, Vontz G, Roelofs J (2016) Starvation induces proteasome autophagy with different pathways for core and regulatory particles. J Biol Chem 291:3239–3253
Cohen-Kaplan V, Livneh I, Avni N, Fabre B, Ziv T, Kwon YT, Ciechanover A (2016) p62- and ubiquitin-dependent stress-induced autophagy of the mammalian 26S proteasome. Proc Natl Acad Sci U S A 113:E7490–E7499
Marshall RS, Vierstra RD (2018) Proteasome storage granules protect proteasomes from autophagic degradation upon carbon starvation. eLife 7:e34532
Tanahashi N, Murakami Y, Minami Y, Shimbara N, Hendil KB, Tanaka K (2000) Hybrid proteasomes. Induction by interferon-gamma and contribution to ATP-dependent proteolysis. J Biol Chem 275:14336–14345
Wang X, Yen J, Kaiser P, Huang L (2010) Regulation of the 26S proteasome complex during oxidative stress. Sci Signal 3:ra88
Grune T, Catalgol B, Licht A, Ermak G, Pickering AM, Ngo JK, Davies KJA (2011) HSP70 mediates dissociation and reassociation of the 26S proteasome during adaptation to oxidative stress. Free Radic Biol Med 51:1355–1364
Jung T, Höhn A, Grune T (2014) The proteasome and the degradation of oxidized proteins: Part III. Redox regulation of the proteasomal system. Redox Biol 2:388–394
Livnat-Levanon N, Kevei E, Kleifeld O, Krutauz D, Segref A et al (2014) Reversible 26S proteasome disassembly upon mitochondrial stress. Cell Rep 7:1371–1380
Wang X, Chemmama IEE, Yu C, Huszagh A, Xu Y et al (2017) The proteasome-interacting Ecm29 protein disassembles the 26S proteasome in response to oxidative stress. J Biol Chem 292:16310–16320
Pickering AM, Davies KJA (2012) Differential roles of proteasome and immunoproteasome regulators Pa28αβ, Pa28γ and Pa200 in the degradation of oxidized proteins. Arch Biochem Biophys 523:181–190
Raynes R, Pomatto LCD, Davies KJA (2016) Degradation of oxidized proteins by the proteasome: distinguishing between the 20S, 26S, and immunoproteasome proteolytic pathways. Mol Asp Med 50:41–55
Shibatani T, Carlson EJ, Larabee F, McCormack AL, Früh K, Skach WR (2006) Global organization and function of mammalian cytosolic proteasome pools: implications for PA28 and 19S regulatory complexes. Mol Biol Cell 17:4962–4971
Welk V, Coux O, Kleene V, Abeza C, Trümbach D, Eickelberg O, Meiners S (2016) Inhibition of proteasome activity induces formation of alternative proteasome complexes. J Biol Chem 291:13147–13159
Groll M, Bajorek M, Köhler A, Moroder L, Rubin DM et al (2000) A gated channel into the proteasome core particle. Nat Struct Biol 7:1062–1067
Savulescu AF, Glickman MH (2011) Proteasome activator 200: the heat is on… . Mol Cell Proteomics 10:R110.006890
Li X, Thompson D, Kumar B, Demartino GN (2014) Molecular and cellular roles of PI31 (PSMF1) in regulation of proteasome function. J Biol Chem 289:17392–17405
Smith DM, Chang SC, Park S, Finley D, Cheng Y, Goldberg AL (2007) Docking of the proteasomal ATPases’ carboxyl termini in the 20S proteasome’s alpha ring opens the gate for substrate entry. Mol Cell 27:731–744
Gillette TG, Kumar B, Thompson D, Slaughter CA, DeMartino GN (2008) Differential roles of the C-termini of AAA subunits of PA700 (19S regulator) in asymmetric assembly and activation of the 26s proteasome. J Biol Chem 283:31813–31822
Whitby FG, Masters EI, Kramer L, Knowlton JR, Yao Y, Wang CC, Hill CP (2000) Structural basis for the activation of 20S proteasomes by 11S regulators. Nature 408:115–120
Förster A, Masters EI, Whitby FG, Robinson H, Hill CP (2005) The 1.9 A structure of a proteasome-11S activator complex and implications for proteasome-PAN/PA700 interactions. Mol Cell 18:589–599
Stadtmueller BM, Hill CP (2011) Proteasome activators. Mol Cell 41:8–19
Kish-Trier E, Hill CP (2013) Structural biology of the proteasome. Annu Rev Biophys 42:29–49
Dange T, Smith D, Noy T, Rommel PC, Jurzitza L et al (2011) Blm10 protein promotes proteasomal substrate turnover by an active gating mechanism. J Biol Chem 286:42830–42839
Toste Rêgo A, da Fonseca PCA (2019) Characterization of fully recombinant human 20S and 20S-PA200 proteasome complexes. Mol Cell. https://doi.org/10.1016/j.molcel.2019.07.014
Opoku-Nsiah KA, Gestwicki JE (2018) Aim for the core: suitability of the ubiquitin-independent 20S proteasome as a drug target in neurodegeneration. Transl Res 198:48–57
Kisselev AF, Kaganovich D, Goldberg AL (2002) Binding of hydrophobic peptides to several non-catalytic sites promotes peptide hydrolysis by all active sites of 20 S proteasomes. Evidence for peptide-induced channel opening in the alpha-rings. J Biol Chem 277:22260–22270
Tanaka K, Yoshimura T, Kumatori A, Ichihara A, Ikai A et al (1988) Proteasomes (multi-protease complexes) as 20 S ring-shaped particles in a variety of eukaryotic cells. J Biol Chem 263:16209–16217
Orlowski M (2001) Selective activation of the 20 S proteasome (multicatalytic proteinase complex) by histone h3. Biochemistry 40:15318–15326
Mayer-Kuckuk P, Ullrich O, Ziegler M, Grune T, Schweiger M (1999) Functional interaction of poly(ADP-ribose) with the 20S proteasome in vitro. Biochem Biophys Res Commun 259:576–581
Tanaka K, Yoshimura T, Ichihara A (1989) Role of substrate in reversible activation of proteasomes (multi-protease complexes) by sodium dodecyl sulfate. J Biochem (Tokyo) 106:495–500
Hirano H, Kimura Y, Kimura A (2016) Biological significance of co- and post-translational modifications of the yeast 26S proteasome. J Proteome 134:37–46
Scruggs SB, Zong NC, Wang D, Stefani E Ping P (2012) Post-translational modification of cardiac proteasomes: functional delineation enabled by proteomics. Am J Physiol Heart Circ Physiol 303:H9–H18.
Tanaka K, Yoshimura T, Tamura T, Fujiwara T, Kumatori A, Ichihara A (1990) Possible mechanism of nuclear translocation of proteasomes. FEBS Lett 271:41–46
Rivett AJ (1998) Intracellular distribution of proteasomes. Curr Opin Immunol 10:110–114
Rivett AJ, Bose S, Brooks P, Broadfoot KI (2001) Regulation of proteasome complexes by gamma-interferon and phosphorylation. Biochimie 83:363–366
VerPlank JJS, Goldberg AL (2017) Regulating protein breakdown through proteasome phosphorylation. Biochem J 474:3355–3371
Guo X, Huang X, Chen MJ (2017) Reversible phosphorylation of the 26S proteasome. Protein Cell 8:255–272
Baraibar MA, Friguet B (2012) Changes of the proteasomal system during the aging process. Prog Mol Biol Transl Sci 109:249–275
Ventadour S, Jarzaguet M, Wing SS, Chambon C, Combaret L et al (2007) A new method of purification of proteasome substrates reveals polyubiquitination of 20 S proteasome subunits. J Biol Chem 282:5302–5309
Fabre B, Lambour T, Delobel J, Amalric F, Monsarrat B, Burlet-Schiltz O, Bousquet-Dubouch MP (2013) Subcellular distribution and dynamics of active proteasome complexes unraveled by a workflow combining in vivo complex cross-linking and quantitative proteomics. Mol Cell Proteomics 12:687–699
Pal JK, Gounon P, Grossi de Sa MF, Scherrer K (1988) Presence and distribution of specific prosome antigens change as a function of embryonic development and tissue-type differentiation in Pleurodeles waltl. J Cell Sci 90:555–567
Amsterdam A, Pitzer F, Baumeister W (1993) Changes in intracellular localization of proteasomes in immortalized ovarian granulosa cells during mitosis associated with a role in cell cycle control. Proc Natl Acad Sci USA 90:99–103
Palmer A, Mason GG, Paramio JM, Knecht E, Rivett AJ (1994) Changes in proteasome localization during the cell cycle. Eur J Cell Biol 64:163–175
Nakamura A, Kitami T, Mori H, Mizuno Y, Hattori N (2006) Nuclear localization of the 20S proteasome subunit in Parkinson’s disease. Neurosci Lett 406:43–48
Reits EA, Benham AM, Plougastel B, Neefjes J, Trowsdale J (1997) Dynamics of proteasome distribution in living cells. EMBO J 16:6087–6094
Laporte D, Salin B, Daignan-Fornier B, Sagot I (2008) Reversible cytoplasmic localization of the proteasome in quiescent yeast cells. J Cell Biol 181:737–745
Rivett AJ, Palmer A, Knecht E (1992) Electron microscopic localization of the multicatalytic proteinase complex in rat liver and in cultured cells. J Histochem Cytochem 40:1165–1172
Sikder D, Johnston SA, Kodadek T (2006) Widespread, but non-identical, association of proteasomal 19 and 20 S proteins with yeast chromatin. J Biol Chem 281:27346–27355
Grossi de Sa MF, Martins de Sa C, Harper F, Olink-Coux M, Huesca M, Scherrer K (1988) The association of prosomes with some of the intermediate filament networks of the animal cell. J Cell Biol 107:1517–1530
Olink-Coux M, Arcangeletti C, Pinardi F, Minisini R, Huesca M, Chezzi C, Scherrer K (1994) Cytolocation of prosome antigens on intermediate filament subnetworks of cytokeratin, vimentin and desmin type. J Cell Sci 107:353–366
Hsu MT, Guo CL, Liou AY, Chang TY, Ng MC et al (2015) Stage-dependent axon transport of proteasomes contributes to axon development. Dev Cell 35:418–431
Liu K, Jones S, Minis A, Rodriguez J, Molina H, Steller H (2019) PI31 is an adaptor protein for proteasome transport in axons and required for synaptic development. Dev Cell 50:509–524
Wójcik C, DeMartino GN (2003) Intracellular localization of proteasomes. Int J Biochem Cell Biol 35:579–589
Kopito RR (2000) Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol 10:524–530
Ramachandran KV, Margolis SS (2017) A mammalian nervous-system-specific plasma membrane proteasome complex that modulates neuronal function. Nat Struct Mol Biol 24:419–430
Bochmann I, Ebstein F, Lehmann A, Wohlschlaeger J, Sixt SU, Kloetzel PM, Dahlmann B (2014) T lymphocytes export proteasomes by way of microparticles: a possible mechanism for generation of extracellular proteasomes. J Cell Mol Med 18:59–68
Bec N, Bonhoure A, Henry L, Berry L, Larroque C et al (2019) Proteasome 19S RP and translation preinitiation complexes are secreted within exosomes upon serum starvation. Traffic 20:516–536
Henry L, Fabre C, Guiraud I, Bastide S, Fabbro-Peray P et al (2013) Clinical use of p-proteasome in discriminating metastatic melanoma patients: comparative study with LDH, MIA and S100B protein. Int J Cancer 133:142–148
Jiang TX, Zhao M, Qiu XB (2018) Substrate receptors of proteasomes. Biol Rev 93:1765–1777
Fort P, Kajava AV, Delsuc FF, Coux O (2015) Evolution of proteasome regulators in eukaryotes. Genome Biol Evol 7:1363–1379
Ciechanover A (2005) Proteolysis: from the lysosome to ubiquitin and the proteasome. Nat Rev Mol Cell Biol 6:79–87
Rousseau A, Bertolotti A (2018) Regulation of proteasome assembly and activity in health and disease. Nat Rev Mol Cell Biol 19:697–712
Collins GA, Goldberg AL (2017) The logic of the 26S proteasome. Cell 169:792–806
Xue S, Barna M (2012) Specialized ribosomes: a new frontier in gene regulation and organismal biology. Nat Rev Mol Cell Biol 13:355–369
Emmott E, Jovanovic M, Slavov N (2019) Ribosome stoichiometry: from form to function. Trends Biochem Sci 44:95–109
Bard JAM, Goodall EA, Greene ER, Jonsson E, Dong KC, Martin A (2018) Structure and function of the 26S proteasome. Annu Rev Biochem 87:697–724
Eisele MR, Reed RG, Rudack T, Schweitzer A, Beck F et al (2018) Expanded coverage of the 26S proteasome conformational landscape reveals mechanisms of peptidase gating. Cell Rep 24:1301–1315.e5
Matyskiela ME, Lander GC, Martin A (2013) Conformational switching of the 26S proteasome enables substrate degradation. Nat Struct Mol Biol 20:781–788
Finley D, Chen X, Walters KJ (2015) Gates, channels, and switches: elements of the proteasome machine. Trends Biochem Sci 41:1–17
Navon A, Goldberg AL (2001) Proteins are unfolded on the surface of the ATPase ring before transport into the proteasome. Mol Cell 8:1339–1349
Lander GC, Estrin E, Matyskiela ME, Bashore C, Nogales E, Martin A (2012) Complete subunit architecture of the proteasome regulatory particle. Nature 482:186–191
Asano S, Fukuda Y, Beck F, Aufderheide A, Förster F, Danev R, Baumeister W (2015) A molecular census of 26. Science 347:439–443
Dambacher CM, Worden EJ, Herzik MA, Martin A, Lander GC (2016) Atomic structure of the 26S proteasome lid reveals the mechanism of deubiquitinase inhibition. eLife 5:1–17
de la Peña AH, Goodall EA, Gates SN, Lander GC, Martin A (2018) Substrate-engaged 26S proteasome structures reveal mechanisms for ATP-hydrolysis-driven translocation. Science 362:eaav0725
Livneh I, Cohen-Kaplan V, Cohen-Rosenzweig C, Avni N, Ciechanover A (2016) The life cycle of the 26S proteasome: from birth, through regulation and function, and onto its death. Cell Res 26:869–885
Princiotta MF, Finzi D, Qian SB, Gibbs J, Schuchmann S et al (2003) Quantitating protein synthesis, degradation, and endogenous antigen processing. Immunity 18:343–354
Brooks P, Fuertes G, Murray RZ, Bose S, Knecht E et al (2000) Subcellular localization of proteasomes and their regulatory complexes in mammalian cells. Biochem J 346:155–161
Gerhardt C, Leu T, Lier JM, Rüther U (2016) The cilia-regulated proteasome and its role in the development of ciliopathies and cancer. Cilia 5:14
Gerhardt C, Lier JM, Burmühl S, Struchtrup A, Deutschmann K et al (2015) The transition zone protein Rpgrip1l regulates proteasomal activity at the primary cilium. J Cell Biol 210:115–133
Liu YP, Tsai IC, Morleo M, Oh EC, Leitch CC et al (2014) Ciliopathy proteins regulate paracrine signaling by modulating proteasomal degradation of mediators. J Clin Invest 124:2059–2070
Bingol B, Schuman EM (2006) Activity-dependent dynamics and sequestration of proteasomes in dendritic spines. Nature 441:1144–1148
Enenkel C (2018) The paradox of proteasome granules. Curr Genet 64:137–140
Albert S, Schaffer M, Beck F, Mosalaganti S, Asano S et al (2017) Proteasomes tether to two distinct sites at the nuclear pore complex. Proc Natl Acad Sci USA 114:13726–13731
Protter DSW, Parker R (2016) Principles and properties of stress granules. Trends Cell Biol 26:668–679
Turakhiya A, Meyer SR, Marincola G, Böhm S, Vanselow JT et al (2018) ZFAND1 recruits p97 and the 26S proteasome to promote the clearance of arsenite-induced stress granules. Mol Cell 70:906–919
Johnston JA, Ward CL, Kopito RR (1998) Aggresomes: a cellular response to misfolded proteins. J Cell Biol 143:1883–1898
Guo Q, Lehmer C, Martínez-Sánchez A, Rudack T, Beck F et al (2018) In situ structure of neuronal C9orf72 Poly-GA aggregates reveals proteasome recruitment. Cell 172:696–705
Zhang Y, Nicholatos J, Dreier JR, Ricoult SJH, Widenmaier SB et al (2014) Coordinated regulation of protein synthesis and degradation by mTORC1. Nature 513:440–443
Liu G, Rogers J, Murphy CT, Rongo C (2011) EGF signalling activates the ubiquitin proteasome system to modulate C. elegans lifespan. EMBO J 30:2990–3003
Rieckmann JC, Geiger R, Hornburg D, Wolf T, Kveler K et al (2017) Social network architecture of human immune cells unveiled by quantitative proteomics. Nat Immunol 18:583–593
Tsvetkov P, Mendillo ML, Zhao J, Carette JE, Merrill PH et al (2015) Compromising the 19S proteasome complex protects cells from reduced flux through the proteasome. eLife 4:e08467
Acosta-Alvear D, Cho MY, Wild T, Buchholz TJ, Lerner AG et al (2015) Paradoxical resistance of multiple myeloma to proteasome inhibitors by decreased levels of 19S proteasomal subunits. eLife 4:e08153
Tsvetkov P, Sokol E, Jin D, Brune Z, Thiru P et al (2016) Suppression of 19S proteasome subunits marks emergence of an altered cell state in diverse cancers. Proc Natl Acad Sci USA 114:382–387
Cohen-Kaplan V, Ciechanover A, Livneh I (2017) Stress-induced polyubiquitination of proteasomal ubiquitin receptors targets the proteolytic complex for autophagic degradation. Autophagy 13:759–760
Budenholzer L, Cheng CL, Li Y, Hochstrasser M (2017) Proteasome structure and assembly. J Mol Biol 429:3500–3524
Rousseau A, Bertolotti A (2016) An evolutionarily conserved pathway controls proteasome homeostasis. Nature 536:184–189
Wang X, Jiang B, Zhang Y (2016) Gankyrin regulates cell signaling network. Tumour Biol 37:5675–5682
Pathare GR, Nagy I, Bohn S, Unverdorben P, Hubert A et al (2012) The proteasomal subunit Rpn6 is a molecular clamp holding the core and regulatory subcomplexes together. Proc Natl Acad Sci USA 109:149–154
Vilchez D, Boyer L, Morantte I, Lutz M, Merkwirth C et al (2012) Increased proteasome activity in human embryonic stem cells is regulated by PSMD11. Nature 489:304–308
Semren N, Welk V, Korfei M, Keller IE, Fernandez IE et al (2015) Regulation of 26S proteasome activity in pulmonary fibrosis. Am J Respir Crit Care Med 192:1089–1101
Segref A, Kevei É, Pokrzywa W, Schmeisser K, Mansfeld J et al (2014) Pathogenesis of human mitochondrial diseases is modulated by reduced activity of the ubiquitin/proteasome system. Cell Metab 19:642–652
Yu C, Wang X, Huszagh AS, Viner R, Novitsky EJ, Rychnovsky SD, Huang L (2019) Probing H2O2-mediated structural dynamics of the human 26S proteasome using quantitative cross-linking mass spectrometry (QXL-MS). Mol Cell Proteomics 18:954–967
Kammerl IE, Caniard A, Merl-Pham J, Ben-Nissan G, Mayr CH et al (2019) Dissecting the molecular effects of cigarette smoke on proteasome function. J Proteome 193:1–9
Day SM, Divald A, Wang P, Davis F, Bartolone S, Jones R, Powell SR (2013) Impaired assembly and post-translational regulation of 26S proteasome in human end-stage heart failure. Circ Heart Fail 6:544–549
Barroso-Chinea P, Thiolat ML, Bido S, Martinez A, Doudnikoff E et al (2015) D1 dopamine receptor stimulation impairs striatal proteasome activity in Parkinsonism through 26S proteasome disassembly. Neurobiol Dis 78:77–87
Kammerl IE, Dann A, Mossina A, Brech D, Lukas C et al (2016) Impairment of immunoproteasome function by cigarette smoke and in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 193:1230–1241
Silva GM, Netto LES, Discola KF, Piassa-Filho GM, Pimenta DC, Bárcena JA, Demasi M (2008) Role of glutaredoxin 2 and cytosolic thioredoxins in cysteinyl-based redox modification of the 20S proteasome. FEBS J 275:2942–2955
Wang D, Fang C, Zong NC, Liem DA, Cadeiras M et al (2013) Regulation of acetylation restores proteolytic function of diseased myocardium in mouse and human. Mol Cell Proteomics 12:3793–3802
Lokireddy S, Kukushkin NV, Goldberg AL (2015) cAMP-induced phosphorylation of 26S proteasomes on Rpn6/PSMD11 enhances their activity and the degradation of misfolded proteins. Proc Natl Acad Sci USA 112:E7176–E7185
VerPlank JJS, Lokireddy S, Zhao J, Goldberg AL (2019) 26S Proteasomes are rapidly activated by diverse hormones and physiological states that raise cAMP and cause Rpn6 phosphorylation. Proc Natl Acad Sci USA 116:4228–4237
Guo X, Wang X, Wang Z, Banerjee S, Yang J, Huang L, Dixon JE (2015) Site-specific proteasome phosphorylation controls cell proliferation and tumorigenesis. Nat Cell Biol 18:1–47
Xu J, Wang S, Zhang M, Wang Q, Asfa S, Zou MH (2012) Tyrosine nitration of PA700 links proteasome activation to endothelial dysfunction in mouse models with cardiovascular risk factors. PloS One 7:e29649
Tsvetkov P, Myers N, Eliav R, Adamovich Y, Hagai T et al (2014) NADH binds and stabilizes the 26S proteasomes independent of ATP. J Biol Chem 289:11272–11281
Zhang F, Su K, Yang X, Bowe DB, Paterson AJ, Kudlow JE (2003) O-GlcNAc modification is an endogenous inhibitor of the proteasome. Cell 115:715–725
Lam YA, Pickart CM, Alban A, Landon M, Jamieson C et al (2000) Inhibition of the ubiquitin-proteasome system in Alzheimer’s disease. Proc Natl Acad Sci USA 97:9902–9906
Bence NF, Sampat RM, Kopito RR (2001) Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292:1552–1555
Powers ET, Morimoto RI, Dillin A, Kelly JW, Balch WE (2009) Biological and chemical approaches to diseases of proteostasis deficiency. Annu Rev Biochem 78:959–991
Balch WE, Sznajder JI, Budinger S, Finley D, Laposky AD et al (2014) Malfolded protein structure and proteostasis in lung diseases. Am J Respir Crit Care Med 189:96–103
Kitamura A, Inada N, Kubota H, Matsumoto G, Kinjo M, Morimoto RI, Nagata K (2014) Dysregulation of the proteasome increases the toxicity of ALS-linked mutant SOD1. Genes Cells 19:209–224
Kipen HM, Gandhi S, Rich DQ, Ohman-Strickland P, Laumbach R et al (2011) Acute decreases in proteasome pathway activity after inhalation of fresh diesel exhaust or secondary organic aerosol. Environ Health Perspect 119:658–663
van Rijt SH, Keller IE, John G, Kohse K, Yildirim AÖ, Eickelberg O, Meiners S (2012) Acute cigarette smoke exposure impairs proteasome function in the lung. Am J Physiol Lung Cell Mol Physiol 303:L814–L823
Gorbea C, Goellner GM, Teter K, Holmes RK, Rechsteiner M (2004) Characterization of mammalian Ecm29, a 26 S proteasome-associated protein that localizes to the nucleus and membrane vesicles. J Biol Chem 279:54849–54861
Kajava AV, Gorbea C, Ortega J, Rechsteiner M, Steven AC (2004) New HEAT-like repeat motifs in proteins regulating proteasome structure and function. J Struct Biol 146:425–430
Leggett DS, Hanna J, Borodovsky A, Crosas B, Schmidt M et al (2002) Multiple associated proteins regulate proteasome structure and function. Mol Cell 10:495–507
Kleijnen MF, Roelofs J, Park S, Hathaway NA, Glickman M, King RW, Finley D (2007) Stability of the proteasome can be regulated allosterically through engagement of its proteolytic active sites. Nat Struct Mol Biol 14:1180–1188
Lee SYC, De la Mota-Peynado A, Roelofs J (2011) Loss of Rpt5 protein interactions with the core particle and Nas2 protein causes the formation of faulty proteasomes that are inhibited by Ecm29 protein. J Biol Chem 286:36641–36651
Wani PS, Suppahia A, Capalla X, Ondracek A, Roelofs J (2016) Phosphorylation of the C-terminal tail of proteasome subunit α7 is required for binding of the proteasome quality control factor Ecm29. Sci Rep 6:27873
Niewienda A, Janek K, Jechow K, Enenkel C, Lehmann A (2010) Ecm29 fulfils quality control functions in proteasome assembly. Mol Cell 38:879–888
Park S, Kim W, Tian G, Gygi SP, Finley D (2011) Structural defects in the regulatory particle-core particle interface of the proteasome induce a novel proteasome stress response. J Biol Chem 286:36652–36666
De La Mota-Peynado A, Lee SYCC, Pierce BM, Wani P, Singh CR, Roelofs J (2013) The proteasome-associated protein Ecm29 inhibits proteasomal ATPase activity and in vivo protein degradation by the proteasome. J Biol Chem 288:29467–29481
Bousquet-Dubouch MP, Nguen S, Bouyssié D, Burlet-Schiltz O, French SW, Monsarrat B, Bardag-Gorce F (2009) Chronic ethanol feeding affects proteasome-interacting proteins. Proteomics 9:3609–3622
Haratake K, Sato A, Tsuruta F, Chiba T (2016) KIAA0368-deficiency affects disassembly of 26S proteasome under oxidative stress condition. J Biochem (Tokyo) 159:609–618
Gorbea C, Pratt G, Ustrell V, Bell R, Sahasrabudhe S, Hughes RE, Rechsteiner M (2010) A protein interaction network for Ecm29 links the 26 S proteasome to molecular motors and endosomal components. J Biol Chem 285:31616–31633
Gorbea C, Rechsteiner M, Vallejo JG, Bowles NE (2013) Depletion of the 26S proteasome adaptor Ecm29 increases toll-like receptor 3 signaling. Sci Signal 6:ra86
Zacharakis N, Chinnasamy H, Black M, Xu H, Lu YC et al (2018) Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer. Nat Med 24:724–730
Miettinen TP, Peltier J, Härtlova A, Gierliński M, Jansen VM, Trost M, Björklund M (2018) Thermal proteome profiling of breast cancer cells reveals proteasomal activation by CDK4/6 inhibitor palbociclib. EMBO J 37:e98359
Ishida Y, Yamazaki K, Kato M, Goto Y, Naya Y et al (2015) MicroRNA expression signature of castration-resistant prostate cancer: the microRNA-221/222 cluster functions as a tumour suppressor and disease progression marker. Br J Cancer 113:1055–1065
Verma R, Chen S, Feldman R, Schieltz D, Yates J, Dohmen J, Deshaies RJ (2000) Proteasomal proteomics: identification of nucleotide-sensitive proteasome-interacting proteins by mass spectrometric analysis of affinity-purified proteasomes. Mol Biol Cell 11:3425–3439
Xie Y, Varshavsky A (2000) Physical association of ubiquitin ligases and the 26S proteasome. Proc Natl Acad Sci USA 97:2497–2502
Xie Y, Varshavsky A (2002) UFD4 lacking the proteasome-binding region catalyses ubiquitination but is impaired in proteolysis. Nat Cell Biol 4:1003–1007
Kulikov R, Letienne J, Kaur M, Grossman SR, Arts J, Blattner C (2010) Mdm2 facilitates the association of p53 with the proteasome. Proc Natl Acad Sci USA 107:10038–10043
Kühnle S, Martínez-Noël G, Leclere F, Hayes SD, Harper JW, Howley PM (2018) Angelman syndrome-associated point mutations in the Zn2+-binding N-terminal (AZUL) domain of UBE3A ubiquitin ligase inhibit binding to the proteasome. J Biol Chem 293:18387–18399
Crosas B, Hanna J, Kirkpatrick DS, Zhang DP, Tone Y et al (2006) Ubiquitin chains are remodeled at the proteasome by opposing ubiquitin ligase and deubiquitinating activities. Cell 127:1401–1413
Harrigan JA, Jacq X, Martin NM, Jackson SP (2018) Deubiquitylating enzymes and drug discovery: emerging opportunities. Nat Rev Drug Discov 17:57–78
Lee BH, Lee MJ, Park S, Oh DC, Elsasser S et al (2010) Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature 467:179–184
Zhang Z, Krutchinsky A, Endicott S, Realini C, Rechsteiner M, Standing KG (1999) Proteasome activator 11S REG or PA28: recombinant REG alpha/REG beta hetero-oligomers are heptamers. Biochemistry 38:5651–5658
Huber EMM, Groll M (2017) The mammalian proteasome activator PA28 forms an asymmetric α4β3 complex. Structure 25:1473–1480.e3
Preckel T, Fung-Leung WP, Cai Z, Vitiello A, Salter-Cid L et al (1999) Impaired immunoproteasome assembly and immune responses in PA28-/- mice. Science 286:2162–2165
Cascio P (2014) PA28αβ: the enigmatic magic ring of the proteasome? Biomolecules 4:566–584
Mao I, Liu J, Li X, Luo H (2008) REGgamma, a proteasome activator and beyond? Cell Mol Life Sci 65:3971–3980
Knowlton JR, Johnston SC, Whitby FG, Realini C, Zhang Z, Rechsteiner M, Hill CP (1997) Structure of the proteasome activator REGalpha (PA28alpha). Nature 390:639–643
Realini C, Jensen CC, Zhang Z, Johnston SC, Knowlton JR, Hill CP, Rechsteiner M (1997) Characterization of recombinant REGalpha, REGbeta, and REGgamma proteasome activators. J Biol Chem 272:25483–25492
Xie SC, Metcalfe RD, Hanssen E, Yang T, Gillett DL et al (2019) The structure of the PA28-20S proteasome complex from Plasmodium falciparum and implications for proteostasis. Nat Microbiol 4:1990–2000
Minami Y, Kawasaki H, Minami M, Tanahashi N, Tanaka K, Yahara I (2000) A critical role for the proteasome activator PA28 in the Hsp90-dependent protein refolding. J Biol Chem 275:9055–9061
Minami M, Shinozaki F, Suzuki M, Yoshimatsu K, Ichikawa Y, Minami Y (2006) The proteasome activator PA28 functions in collaboration with Hsp90 in vivo. Biochem Biophys Res Commun 344:1315–1319
Kudriaeva A, Kuzina ES, Zubenko O, Smirnov IV, Belogurov A (2019) Charge-mediated proteasome targeting. FASEB J 33:6852–6866
Cascio P, Call M, Petre BM, Walz T, Goldberg AL (2002) Properties of the hybrid form of the 26S proteasome containing both 19S and PA28 complexes. EMBO J 21:2636–2645
Li J, Rechsteiner M (2001) Molecular dissection of the 11S REG (PA28) proteasome activators. Biochimie 83:373–383
Sugiyama M, Sahashi H, Kurimoto E, Takata S, Yagi H et al (2013) Spatial arrangement and functional role of α subunits of proteasome activator PA28 in hetero-oligomeric form. Biochem Biophys Res Commun 432:141–145
Rock KL, York IA, Saric T, Goldberg AL (2002) Protein degradation and the generation of MHC class I-presented peptides. Adv Immunol 80:1–70
Murata S, Udono H, Tanahashi N, Hamada N, Watanabe K et al (2001) Immunoproteasome assembly and antigen presentation in mice lacking both PA28alpha and PA28beta. EMBO J 20:5898–5907
Barton LF, Runnels HA, Schell TD, Cho Y, Gibbons R et al (2004) Immune defects in 28-kDa proteasome activator gamma-deficient mice. J Immunol 172:3948–3954
de Graaf N, van Helden MJG, Textoris-Taube K, Chiba T, Topham DJ et al (2011) PA28 and the proteasome immunosubunits play a central and independent role in the production of MHC class I-binding peptides in vivo. Eur J Immunol 41:926–935
Raule M, Cerruti F, Benaroudj N, Migotti R, Kikuchi J et al (2014) PA28αβ reduces size and increases hydrophilicity of 20S immunoproteasome peptide products. Chem Biol 21:470–480
Yamano T, Sugahara H, Mizukami S, Murata S, Chiba T et al (2008) Allele-selective effect of PA28 in MHC class I antigen processing. J Immunol 181:1655–1664
Seeger M, Ferrell K, Frank R, Dubiel W (1997) HIV-1 tat inhibits the 20 S proteasome and its 11 S regulator-mediated activation. J Biol Chem 272:8145–8148
Stohwasser R, Holzhütter HG, Lehmann U, Henklein P, Kloetzel PM (2003) Hepatitis B virus HBx peptide 116-138 and proteasome activator PA28 compete for binding to the proteasome alpha4/MC6 subunit. Biol Chem 384:39–49
De Leo A, Matusali G, Arena G, Di Renzo L, Mattia E (2010) Epstein-Barr virus lytic cycle activation alters proteasome subunit expression in Burkitt’s lymphoma cells. Biol Chem 391:1041–1046
Gu Y, Xu K, Torre C, Samur M, Barwick BG et al (2017) 14-3-3ζ binds the proteasome, limits proteolytic function, and enhances sensitivity to proteasome inhibitors. Leukemia 32:744–751
Murata S, Kawahara H, Tohma S, Yamamoto K, Kasahara M et al (1999) Growth retardation in mice lacking the proteasome activator PA28gamma. J Biol Chem 274:38211–38215
Zhang Y, Liu S, Zuo Q, Wu L, Ji L et al (2015) Oxidative challenge enhances REGγ-proteasome-dependent protein degradation. Free Radic Biol Med 82:42–49
Huang L, Haratake K, Miyahara H, Chiba T (2016) Proteasome activators, PA28γ and PA200, play indispensable roles in male fertility. Sci Rep 6:23171
Levy-Barda A, Lerenthal Y, Davis AJ, Chung YM, Essers J et al (2011) Involvement of the nuclear proteasome activator PA28γ in the cellular response to DNA double-strand breaks. Cell Cycle 10:4300–4310
Li L, Zhao D, Wei H, Yao L, Dang Y et al (2013) REGγ deficiency promotes premature aging via the casein kinase 1 pathway. Proc Natl Acad Sci USA 110:11005–11010
Baldin V, Militello M, Thomas Y, Doucet C, Fic W et al (2008) A novel role for PA28gamma-proteasome in nuclear speckle organization and SR protein trafficking. Mol Biol Cell 19:1706–1716
Cioce M, Boulon S, Matera AG, Lamond AI (2006) UV-induced fragmentation of Cajal bodies. J Cell Biol 175:401–413
Zannini L, Buscemi G, Fontanella E, Lisanti S, Delia D (2009) REGgamma/PA28gamma proteasome activator interacts with PML and Chk2 and affects PML nuclear bodies number. Cell Cycle 8:2399–2407
Fesquet D, Llères D, Viganò C, Méchali F, Boulon S et al (2019) The 20S proteasome activator PA28γ controls the compaction of HP1β-linked heterochromatin. bioRxiv. https://doi.org/10.1101/716332
Zannini L, Lecis D, Buscemi G, Carlessi L, Gasparini P et al (2008) REGgamma proteasome activator is involved in the maintenance of chromosomal stability. Cell Cycle 7:504–512
Chen X, Barton LF, Chi Y, Clurman BE, Roberts JM (2007) Ubiquitin-independent degradation of cell-cycle inhibitors by the REGgamma proteasome. Mol Cell 26:843–852
Li X, Amazit L, Long W, Lonard DM, Monaco JJ, O’Malley BW (2007) Ubiquitin- and ATP-independent proteolytic turnover of p21 by the REGgamma-proteasome pathway. Mol Cell 26:831–842
Kobayashi T, Wang J, Al-Ahmadie HA, Abate-Shen C (2013) ARF regulates the stability of p16 protein via REGγ-dependent proteasome degradation. Mol Cancer Res 11:828–833
Li X, Lonard DM, Jung SY, Malovannaya A, Feng Q et al (2006) The SRC-3/AIB1 coactivator is degraded in a ubiquitin- and ATP-independent manner by the REGgamma proteasome. Cell 124:381–392
Ying H, Furuya F, Zhao L, Araki O, West BL et al (2006) Aberrant accumulation of PTTG1 induced by a mutated thyroid hormone beta receptor inhibits mitotic progression. J Clin Invest 116:2972–2984
Furuya F, Ying H, Zhao L, Cheng SY (2007) Novel functions of thyroid hormone receptor mutants: beyond nucleus-initiated transcription. Steroids 72:171–179
Zhang Z, Zhang R (2008) Proteasome activator PA28 gamma regulates p53 by enhancing its MDM2-mediated degradation. EMBO J 27:852–864
Li S, Jiang C, Pan J, Wang X, Jin J et al (2015) Regulation of c-Myc protein stability by proteasome activator REGγ. Cell Death Differ 22:1000–1011
Guo J, Hao J, Jiang H, Jin J, Wu H, Jin Z, Li Z (2017) Proteasome activator subunit 3 promotes pancreatic cancer growth via c-Myc-glycolysis signaling axis. Cancer Lett 386:161–167
Li L, Dang Y, Zhang J, Yan W, Zhai W et al (2015) REGγ is critical for skin carcinogenesis by modulating the Wnt/β-catenin pathway. Nat Commun 6:6875
Moncsek A, Gruner M, Meyer H, Lehmann A, Kloetzel PM, Stohwasser R (2015) Evidence for anti-apoptotic roles of proteasome activator 28γ via inhibiting caspase activity. Apoptosis 20:1211–1228
Araya R, Takahashi R, Nomura Y (2002) Yeast two-hybrid screening using constitutive-active caspase-7 as bait in the identification of PA28gamma as an effector caspase substrate. Cell Death Differ 9:322–328
Okamura T, Taniguchi SI, Ohkura T, Yoshida A, Shimizu H et al (2003) Abnormally high expression of proteasome activator-gamma in thyroid neoplasm. J Clin Endocrinol Metab 88:1374–1383
Wang X, Tu S, Tan J, Tian T, Ran L, Rodier JF, Ren G (2011) REG gamma: a potential marker in breast cancer and effect on cell cycle and proliferation of breast cancer cell. Med Oncol 28:31–41
Zhang M, Gan L, Ren GS (2012) REGγ is a strong candidate for the regulation of cell cycle, proliferation and the invasion by poorly differentiated thyroid carcinoma cells. Braz J Med Biol Res 45:459–465
He J, Cui L, Zeng Y, Wang G, Zhou P et al (2012) REGγ is associated with multiple oncogenic pathways in human cancers. BMC Cancer 12:75
Ali A, Wang Z, Fu J, Ji L, Liu J et al (2013) Differential regulation of the REGγ-proteasome pathway by p53/TGF-β signalling and mutant p53 in cancer cells. Nat Commun 4:2667
Wan ZX, Yuan DM, Zhuo YM, Yi X, Zhou J, Xu ZX, Zhou JL (2014) The proteasome activator PA28γ, a negative regulator of p53, is transcriptionally up-regulated by p53. Int J Mol Sci 15:2573–2584
Xu J, Zhou L, Ji L, Chen F, Fortmann K et al (2016) The REGγ-proteasome forms a regulatory circuit with IκBɛ and NFκB in experimental colitis. Nat Commun 7:10761
Xu X, Liu D, Ji N, Li T, Li L et al (2015) A novel transcript variant of proteasome activator 28γ: identification and function in oral cancer cells. Int J Oncol 47:188–194
Sanchez N, Gallagher M, Lao N, Gallagher C, Clarke C et al (2013) MiR-7 triggers cell cycle arrest at the G1/S transition by targeting multiple genes including Skp2 and Psme3. PloS One 8:e65671
Xiong S, Zheng Y, Jiang P, Liu R, Liu X et al (2014) PA28gamma emerges as a novel functional target of tumour suppressor microRNA-7 in non-small-cell lung cancer. Br J Cancer 110:353–362
Shi Y, Luo X, Li P, Tan J, Wang X, Xiang T, Ren G (2015) miR-7-5p suppresses cell proliferation and induces apoptosis of breast cancer cells mainly by targeting REGγ. Cancer Lett 358:27–36
Chen S, Wang L, Yao X, Chen H, Xu C et al (2017) miR-195-5p is critical in REGγ-mediated regulation of wnt/β-catenin pathway in renal cell carcinoma. Oncotarget 8:63986–64000
Magni M, Ruscica V, Buscemi G, Kim JE, Nachimuthu BT et al (2014) Chk2 and REGγ-dependent DBC1 regulation in DNA damage induced apoptosis. Nucleic Acids Res 42:13150–13160
Hagemann C, Patel R, Blank JL (2003) MEKK3 interacts with the PA28 gamma regulatory subunit of the proteasome. Biochem J 373:71–79
Gao G, Wong J, Zhang J, Mao I, Shravah J et al (2010) Proteasome activator REGgamma enhances coxsackieviral infection by facilitating p53 degradation. J Virol 84:11056–11066
Wu Y, Wang L, Zhou P, Wang G, Zeng Y et al (2011) Regulation of REGγ cellular distribution and function by SUMO modification. Cell Res 21:807–816
Liu J, Wang Y, Li L, Zhou L, Wei H et al (2013) Site-specific acetylation of the proteasome activator REGγ directs its heptameric structure and functions. J Biol Chem 288:16567–16578
Jonik-Nowak B, Menneteau T, Fesquet D, Baldin V, Bonne-Andrea C et al (2018) PIP30/FAM192A is a novel regulator of the nuclear proteasome activator PA28γ. Proc Natl Acad Sci USA 115:E6477–E6486
Xie T, Chen H, Shen S, Huang T, Huang B et al (2019) Proteasome activator REGγ promotes inflammation in Leydig cells via IkBε signaling. Int J Mol Med 43:1961–1968
Sun J, Luan Y, Xiang D, Tan X, Chen H et al (2016) The 11S proteasome subunit PSME3 is a positive feedforward regulator of NF-κB and important for host defense against bacterial pathogens. Cell Rep 14:737–749
Yan Q, Sharma-Kuinkel BK, Deshmukh H, Tsalik EL, Cyr DD et al (2014) Dusp3 and Psme3 are associated with murine susceptibility to Staphylococcus aureus infection and human sepsis. PLoS Pathog 10:e1004149
Wang Q, Gao X, Yu T, Yuan L, Dai J et al (2018) REGγ controls hippo signaling and reciprocal NF-κB-YAP regulation to promote colon cancer. Clin Cancer Res 24:2015–2025
Chen S, Wang Q, Wang L, Chen H, Gao X et al (2018) REGγ deficiency suppresses tumor progression via stabilizing CK1ε in renal cell carcinoma. Cell Death Dis 9:627
Liu J, Yu G, Zhao Y, Zhao D, Wang Y et al (2010) REGgamma modulates p53 activity by regulating its cellular localization. J Cell Sci 123:4076–4084
Kwak J, Tiwari I, Jang KL (2017) Hepatitis C virus core activates proteasomal activator 28 gamma expression via upregulation of p53 levels to control virus propagation. J Gen Virol 98:56–67
Yeom S, Jeong H, Kim SS, Jang KL (2018) Hepatitis B virus X protein activates proteasomal activator 28 gamma expression via upregulation of p53 levels to stimulate virus replication. J Gen Virol 99:655–666
Wang H, Bao W, Jiang F, Che Q, Chen Z et al (2015) Mutant p53 (p53-R248Q) functions as an oncogene in promoting endometrial cancer by up-regulating REGγ. Cancer Lett 360:269–279
Lv Y, Meng B, Dong H, Jing T, Wu N et al (2016) Up-regulation of GSK3β contributes to brain disorders in elderly REGγ-knockout mice. Neuropsychopharmacology 41:1340–1349
Chen H, Gao X, Sun Z, Wang Q, Zuo D et al (2017) REGγ accelerates melanoma formation by regulating Wnt/β-catenin signaling pathway. Exp Dermatol 26:1118–1124
Kanai K, Aramata S, Katakami S, Yasuda K, Kataoka K (2011) Proteasome activator PA28{gamma} stimulates degradation of GSK3-phosphorylated insulin transcription activator MAFA. J Mol Endocrinol 47:119–127
Jiao C, Li L, Zhang P, Zhang L, Li K et al (2020) REGγ ablation impedes dedifferentiation of anaplastic thyroid carcinoma and accentuates radio-therapeutic response by regulating the Smad7-TGF-β pathway. Cell Death Differ 27:497–508
Liu S, Lai L, Zuo Q, Dai F, Wu L et al (2014) PKA turnover by the REGγ-proteasome modulates FoxO1 cellular activity and VEGF-induced angiogenesis. J Mol Cell Cardiol 72:28–38
Xie Y, Li X, Ge J (2019) Expression of REGγ in atherosclerotic plaques and promotes endothelial cells apoptosis via the cyclophilin A pathway indicates functional implications in atherogenesis. Cell Cycle 18:2083–2098
Fan J, Liu L, Liu Q, Cui Y, Yao B et al (2019) CKIP-1 limits foam cell formation and inhibits atherosclerosis by promoting degradation of Oct-1 by REGγ. Nat Commun 10:425
Dong S, Jia C, Zhang S, Fan G, Li Y et al (2013) The REGγ proteasome regulates hepatic lipid metabolism through inhibition of autophagy. Cell Metab 18:380–391
Jiang TX, Zou JB, Zhu QQ, Liu CH, Wang GF et al (2019) SIP/CacyBP promotes autophagy by regulating levels of BRUCE/Apollon, which stimulates LC3-I degradation. Proc Natl Acad Sci USA 116:13404–13413
Bartke T, Pohl C, Pyrowolakis G, Jentsch S (2004) Dual role of BRUCE as an antiapoptotic IAP and a chimeric E2/E3 ubiquitin ligase. Mol Cell 14:801–811
Doueiri R, Anupam R, Kvaratskhelia M, Green KB, Lairmore MD, Green PL (2012) Comparative host protein interactions with HTLV-1 p30 and HTLV-2 p28: insights into difference in pathobiology of human retroviruses. Retrovirology 9:64
Ko NL, Taylor JM, Bellon M, Bai XT, Shevtsov SP, Dundr M, Nicot C (2013) PA28γ is a novel corepressor of HTLV-1 replication and controls viral latency. Blood 121:791–800
Moriishi K, Okabayashi T, Nakai K, Moriya K, Koike K et al (2003) Proteasome activator PA28gamma-dependent nuclear retention and degradation of hepatitis C virus core protein. J Virol 77:10237–10249
Moriishi K, Mochizuki R, Moriya K, Miyamoto H, Mori Y et al (2007) Critical role of PA28gamma in hepatitis C virus-associated steatogenesis and hepatocarcinogenesis. Proc Natl Acad Sci USA 104:1661–1666
Miyamoto H, Moriishi K, Moriya K, Murata S, Tanaka K et al (2007) Involvement of the PA28gamma-dependent pathway in insulin resistance induced by hepatitis C virus core protein. J Virol 81:1727–1735
Ustrell V, Hoffman L, Pratt G, Rechsteiner M (2002) PA200, a nuclear proteasome activator involved in DNA repair. EMBO J 21:3516–3525
Blickwedehl J, McEvoy S, Wong I, Kousis P, Clements J et al (2007) Proteasomes and proteasome activator 200 kDa (PA200) accumulate on chromatin in response to ionizing radiation. Radiat Res 167:663–674
Schmidt M, Haas W, Crosas B, Santamaria PG, Gygi SP, Walz T, Finley D (2005) The HEAT repeat protein Blm10 regulates the yeast proteasome by capping the core particle. Nat Struct Mol Biol 12:294–303
Sadre-Bazzaz K, Whitby FG, Robinson H, Formosa T, Hill CP (2010) Structure of a Blm10 complex reveals common mechanisms for proteasome binding and gate opening. Mol Cell 37:728–735
Ortega J, Bernard Heymann J, Kajava AV, Ustrell V, Rechsteiner M, Steven AC (2005) The axial channel of the 20S proteasome opens upon binding of the PA200 activator. J Mol Biol 346:1221–1227
Fehlker M, Wendler P, Lehmann A, Enenkel C (2003) Blm3 is part of nascent proteasomes and is involved in a late stage of nuclear proteasome assembly. EMBO Rep 4:959–963
Marques AJ, Glanemann C, Ramos PC, Dohmen RJ (2007) The C-terminal extension of the beta7 subunit and activator complexes stabilize nascent 20 S proteasomes and promote their maturation. J Biol Chem 282:34869–34876
Doherty KM, Pride LD, Lukose J, Snydsman BE, Charles R et al (2012) Loss of a 20S proteasome activator in saccharomyces cerevisiae downregulates genes important for genomic integrity, increases DNA damage, and selectively sensitizes cells to agents with diverse mechanisms of action. G3 2:943–959
Tar K, Dange T, Yang C, Yao Y, Bulteau AL et al (2014) Proteasomes associated with the Blm10 activator protein antagonize mitochondrial fission through degradation of the fission protein Dnm1. J Biol Chem 289:12145–12156
Khor B, Bredemeyer AL, Huang CY, Turnbull IR, Evans R et al (2006) Proteasome activator PA200 is required for normal spermatogenesis. Mol Cell Biol 26:2999–3007
Mandemaker IK, Geijer ME, Kik I, Bezstarosti K, Rijkers E et al (2018) DNA damage-induced replication stress results in PA200-proteasome-mediated degradation of acetylated histones. EMBO Rep 19:e45566
Blickwedehl J, Agarwal M, Seong C, Pandita RK, Melendy T et al (2008) Role for proteasome activator PA200 and postglutamyl proteasome activity in genomic stability. Proc Natl Acad Sci USA 105:16165–16170
Blickwedehl J, Olejniczak S, Cummings R, Sarvaiya N, Mantilla A et al (2012) The proteasome activator PA200 regulates tumor cell responsiveness to glutamine and resistance to ionizing radiation. Mol Cancer Res 10:937–944
Wang F, Ma H, Liang WJ, Yang JJ, Wang XQ et al (2017) Lovastatin upregulates microRNA-29b to reduce oxidative stress in rats with multiple cardiovascular risk factors. Oncotarget 8:9021–9034
Rechsteiner M, Hill CP (2005) Mobilizing the proteolytic machine: cell biological roles of proteasome activators and inhibitors. Trends Cell Biol 15:27–33
McCutchen-Maloney SL, Matsuda K, Shimbara N, Binns DD, Tanaka K, Slaughter CA, DeMartino GN (2000) cDNA cloning, expression, and functional characterization of PI31, a proline-rich inhibitor of the proteasome. J Biol Chem 275:18557–18565
Zaiss DMW, Standera S, Kloetzel PMPM, Sijts AJAM (2002) PI31 is a modulator of proteasome formation and antigen processing. Proc Natl Acad Sci USA 99:14344–14349
Bader M, Benjamin S, Wapinski OL, Smith DM, Goldberg AL, Steller H (2011) A conserved F box regulatory complex controls proteasome activity in Drosophila. Cell 145:371–382
Yashiroda H, Toda Y, Otsu S, Takagi K, Mizushima T et al (2014) N-terminal α7 deletion of the proteasome 20S core particle substitutes for yeast PI31 function. Mol Cell Biol 35:141–152
Corridoni D, Shiraishi S, Chapman T, Steevels T, Muraro D et al (2019) NOD2 and TLR2 signal via TBK1 and PI31 to direct cross-presentation and CD8 T cell responses. Front Immunol 10:958
Kirk R, Laman H, Knowles PP, Murray-Rust J, Lomonosov M, Meziane EK, McDonald NQ (2008) Structure of a conserved dimerization domain within the F-box protein Fbxo7 and the PI31 proteasome inhibitor. J Biol Chem 283:22325–22335
Cho-Park PF, Steller H (2013) Proteasome regulation by ADP-ribosylation. Cell 153:614–627
Merzetti EM, Dolomount LA, Staveley BE (2017) The FBXO7 homologue nutcracker and binding partner PI31 in Drosophila melanogaster models of Parkinson’s disease. Genome 60:46–54
Sherva R, Baldwin CT, Inzelberg R, Vardarajan B, Cupples LA et al (2011) Identification of novel candidate genes for Alzheimer’s disease by autozygosity mapping using genome wide SNP data. J Alzheimers Dis 23:349–359
Chaber R, Gurgul A, Wróbel G, Haus O, Tomoń A et al (2017) Whole-genome DNA methylation characteristics in pediatric precursor B cell acute lymphoblastic leukemia (BCP ALL). PloS One 12:e0187422
Gomes AV (2013) Genetics of proteasome diseases. Scientifica 2013:1–30
Liu Y, Ramot Y, Torrelo A, Paller AS, Si N et al (2012) Mutations in proteasome subunit β type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity. Arthritis Rheum 64:895–907
Arima K, Kinoshita A, Mishima H, Kanazawa N, Kaneko T et al (2011) Proteasome assembly defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo-Nishimura syndrome. Proc Natl Acad Sci USA 108:14914–14919
Agarwal AK, Xing C, DeMartino GN, Mizrachi D, Hernandez MD et al (2010) PSMB8 encoding the β5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome. Am J Hum Genet 87:866–872
Kitamura A, Maekawa Y, Uehara H, Izumi K, Kawachi I et al (2011) A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humans. J Clin Immunol 121:4150–4160
Torrelo A, Patel S, Colmenero I, Gurbindo D, Lendínez F et al (2010) Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome. J Am Acad Dermatol 62:489–495
Brehm A, Liu Y, Sheikh A, Marrero B, Omoyinmi E et al (2015) Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production. J Clin Invest 125:4196–4211
Canna SW, Goldbach-Mansky R (2015) New monogenic autoinflammatory diseases—a clinical overview. Semin Immunopathol 37:387–394
Torrelo A (2017) CANDLE syndrome as a paradigm of proteasome-related autoinflammation. Front Immunol 8:927
Shwin KW, Lee CCR, Goldbach-Mansky R (2017) Dermatologic manifestations of monogenic autoinflammatory diseases. Dermatol Clin 35:21–38
Kim H, Sanchez GAM, Goldbach-Mansky R (2016) Insights from Mendelian interferonopathies: comparison of CANDLE, SAVI with AGS, monogenic lupus. J Mol Med 94:1111–1127
McDermott A, Jacks J, Kessler M, Emanuel PD, Gao L (2015) Proteasome-associated autoinflammatory syndromes: advances in pathogeneses, clinical presentations, diagnosis, and management. Int J Dermatol 54:121–129
Sanchez GAM, Reinhardt A, Ramsey S, Wittkowski H, Hashkes PJ et al (2018) JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies. J Clin Invest 128:3041–3052
Boyadzhiev M, Marinov L, Boyadzhiev V, Iotova V, Aksentijevich I, Hambleton S (2019) Disease course and treatment effects of a JAK inhibitor in a patient with CANDLE syndrome. Pediatr Rheumatol Online J 17:19
McDermott A, Jesus AA, Liu Y, Kim P, Jacks J et al (2013) A case of proteasome-associated auto-inflammatory syndrome with compound heterozygous mutations. J Am Acad Dermatol 69:e29–e32
Contreras-Cubas C, Cárdenas-Conejo A, Rodríguez-Velasco A, García-Ortiz H, Orozco L, Baca V (2018) A homozygous mutation in the PSMB8 gene in a case with proteasome-associated autoinflammatory syndrome. Scand J Rheumatol 47:251–254
Shi X, Xiang X, Wang Z, Ma L, Xu Z (2019) Chinese case of Nakajo-Nishimura syndrome with a novel mutation of the PSMB8 gene. J Dermatol 46:e160–e161
Poli MC, Ebstein F, Nicholas SK, de Guzman MM, Forbes LR et al (2018) Heterozygous truncating variants in POMP escape nonsense-mediated decay and cause a unique immune dysregulatory syndrome. Am J Hum Genet 102:1126–1142
de Jesus AA, Brehm A, VanTries R, Pillet P, Parentelli AS et al (2019) Novel proteasome assembly chaperone mutations in PSMG2/PAC2, cause the autoinflammatory interferonopathy, CANDLE/PRAAS4. J Allergy Clin Immunol 143:1939–1943.e8
Kanazawa N (2012) Nakajo-Nishimura syndrome: an autoinflammatory disorder showing pernio-like rashes and progressive partial lipodystrophy. Allergol Int 61:197–206
Sotzny F, Schormann E, Kühlewindt I, Koch A, Brehm A et al (2016) TCF11/Nrf1-mediated induction of proteasome expression prevents cytotoxicity by rotenone. Antioxid Redox Signal 25:870–885
Brehm A, Krüger E (2015) Dysfunction in protein clearance by the proteasome: impact on autoinflammatory diseases. Semin Immunopathol 37:323–333
Honda-Ozaki F, Terashima M, Niwa A, Saiki N, Kawasaki Y et al (2018) Pluripotent stem cell model of Nakajo-Nishimura syndrome untangles proinflammatory pathways mediated by oxidative stress. Stem Cell Reports 10:1835–1850
Kanazawa N, Honda-Ozaki F, Saito MK (2019) Induced pluripotent stem cells representing Nakajo-Nishimura syndrome. Inflamm Regen 39:11
Dahlqvist J, Klar J, Tiwari N, Schuster J, Törmä H et al (2010) A single-nucleotide deletion in the POMP 5′ UTR causes a transcriptional switch and altered epidermal proteasome distribution in KLICK genodermatosis. Am J Hum Genet 86:596–603
Dahlqvist J, Törmä H, Badhai J, Dahl N (2012) siRNA silencing of proteasome maturation protein (POMP) activates the unfolded protein response and constitutes a model for KLICK genodermatosis. PLoS One 7:e29471
Küry S, Besnard T, Ebstein F, Khan TN, Gambin T et al (2017) De novo disruption of the proteasome regulatory subunit PSMD12 causes a syndromic neurodevelopmental disorder. Am J Hum Genet 100:352–363
Korovila I, Hugo M, Castro JP, Weber D, Höhn A, Grune T, Jung T (2017) Proteostasis, oxidative stress and aging. Redox Biol 13:550–567
Hipp MS, Park SH, Hartl FU (2014) Proteostasis impairment in protein-misfolding and -aggregation diseases. Trends Cell Biol 24:506–514
Pajares M, Jiménez-Moreno N, Dias IHK, Debelec B, Vucetic M et al (2015) Redox control of protein degradation. Redox Biol 6:409–420
Jung T, Catalgol B, Grune T (2009) The proteasomal system. Mol Asp Med 30:191–296
Chapple SJ, Siowand RCM, Mann GE (2012) Crosstalk between Nrf2 and the proteasome: therapeutic potential of Nrf2 inducers in vascular disease and aging. Int J Biochem Cell Biol 44:1315–1320
Lefaki M, Papaevgeniou N, Chondrogianni N (2017) Redox regulation of proteasome function. Redox Biol 13:452–458
Ullrich O, Reinheckel T, Sitte N, Hass R, Grune T, Davies KJ (1999) Poly-ADP ribose polymerase activates nuclear proteasome to degrade oxidatively damaged histones. Proc Natl Acad Sci USA 96:6223–6228
Moscovitz O, Ben-Nissan G, Fainer I, Pollack D, Mizrachi L, Sharon M (2015) The Parkinson’s-associated protein DJ-1 regulates the 20S proteasome. Nat Commun 6:6609
Pickering AM, Koop AL, Teoh CY, Ermak G, Grune T, Davies KJA (2010) The immunoproteasome, the 20S proteasome and the PA28αβ proteasome regulator are oxidative-stress-adaptive proteolytic complexes. Biochem J 432:585–595
Hernebring M, Fredriksson A, Liljevald M, Cvijovic M, Norrman K et al (2013) Removal of damaged proteins during ES cell fate specification requires the proteasome activator PA28. Sci Rep 3:1381
Pickering AM, Linder RA, Zhang H, Forman HJ, Davies KJA (2012) Nrf2 dependent induction of proteasome and Pa28αβ regulator is required for adaptation to oxidative stress. J Biol Chem 287:10021–10031
Li J, Powell SR, Wang X (2011) Enhancement of proteasome function by PA28α; overexpression protects against oxidative stress. FASEB J 25:883–893
Lobanova ES, Finkelstein S, Li J, Travis AM, Hao Y et al (2018) Increased proteasomal activity supports photoreceptor survival in inherited retinal degeneration. Nat Commun 9:1738
Zuo Q, Cheng S, Huang W, Bhatti MZ, Xue Y et al (2017) REGγ contributes to regulation of hemoglobin and hemoglobin δ subunit. Oxidative Med Cell Longev 2017:7295319
Seifert U, Bialy LP, Ebstein F, Bech-Otschir D, Voigt A et al (2010) Immunoproteasomes preserve protein homeostasis upon interferon-induced oxidative stress. Cell 142:613–624
Nathan JA, Spinnenhirn V, Schmidtke G, Basler M, Groettrup M, Goldberg AL (2013) Immuno- and constitutive proteasomes do not differ in their abilities to degrade ubiquitinated proteins. Cell 152:1184–1194
Kwak MK, Wakabayashi N, Greenlaw JL, Yamamoto M, Kensler TW (2003) Antioxidants enhance mammalian proteasome expression through the Keap1-Nrf2 signaling pathway. Mol Cell Biol 23:8786–8794
Ostrowska H, Kruszewski K, Kasacka I (2006) Immuno-proteasome subunit LMP7 is up-regulated in the ischemic kidney in an experimental model of renovascular hypertension. Int J Biochem Cell Biol 38:1778–1785
Mihalas BP, Bromfield EG, Sutherland JM, De Iuliis GN, McLaughlin EA, Aitken RJ, Nixon B (2018) Oxidative damage in naturally aged mouse oocytes is exacerbated by dysregulation of proteasomal activity. J Biol Chem 293:18944–18964
Ciechanover A, Kwon YT (2015) Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies. Exp Mol Med 47:e147
Choi ML, Gandhi S (2018) Crucial role of protein oligomerization in the pathogenesis of Alzheimer’s and Parkinson’s diseases. FEBS J 285:3631–3644
Thibaudeau TA, Anderson RT, Smith DM (2018) A common mechanism of proteasome impairment by neurodegenerative disease-associated oligomers. Nat Commun 9:1097
Hipp MS, Patel CN, Bersuker K, Riley BE, Kaiser SE et al (2012) Indirect inhibition of 26S proteasome activity in a cellular model of Huntington’s disease. J Cell Biol 196:573–587
Shen M, Schmitt S, Buac D, Dou QP (2013) Targeting the ubiquitin-proteasome system for cancer therapy. Expert Opin Ther Targets 17:1091–1108
Adams J (2002) Proteasome inhibition: a novel approach to cancer therapy. Trends Mol Med 8:S49–S54
Zhang X, Schulz R, Edmunds S, Krüger E, Markert E et al (2015) MicroRNA-101 suppresses tumor cell proliferation by acting as an endogenous proteasome inhibitor via targeting the proteasome assembly factor POMP. Mol Cell 59:243–257
Tsvetkov P, Adler J, Myers N, Biran A, Reuven N, Shaul Y (2018) Oncogenic addiction to high 26S proteasome level. Cell Death Dis 9:773
Walerych D, Lisek K, Sommaggio R, Piazza S, Ciani Y et al (2016) Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer. Nat Cell Biol 18:897–909
Voutsadakis IA (2017) Proteasome expression and activity in cancer and cancer stem cells. Tumor Biol 39:101042831769224
Tsvetkov P, Detappe A, Cai K, Keys HR, Brune Z et al (2019) Mitochondrial metabolism promotes adaptation to proteotoxic stress. Nat Chem Biol 15:681–689
Tripathi SC, Peters HL, Taguchi A, Katayama H, Wang H et al (2016) Immunoproteasome deficiency is a feature of non-small cell lung cancer with a mesenchymal phenotype and is associated with a poor outcome. Proc Natl Acad Sci USA 113:E1555–E1564
Chen S, Wang L, Xu C, Chen H, Peng B et al (2017) Knockdown of REGγ inhibits proliferation by inducing apoptosis and cell cycle arrest in prostate cancer. Am J Transl Res 9:3787–3795
Liu S, Zheng LL, Zhu YM, Shen HJ, Zhong Q et al (2018) Knockdown of REGγ inhibits the proliferation and migration and promotes the apoptosis of multiple myeloma cells by downregulating NF-κB signal pathway. Hematology Amst Neth 23:277–283
Sun L, Fan G, Shan P, Qiu X, Dong S et al (2016) Regulation of energy homeostasis by the ubiquitin-independent REGγ proteasome. Nat Commun 7:12497
Keller M, Ebstein F, Bürger E, Textoris-Taube K, Gorny X et al (2015) The proteasome immunosubunits, PA28 and ER-aminopeptidase 1 protect melanoma cells from efficient MART-126-35-specific T-cell recognition. Eur J Immunol 45:3257–3268
Cerruti F, Martano M, Petterino C, Bollo E, Morello E et al (2007) Enhanced expression of interferon-gamma-induced antigen-processing machinery components in a spontaneously occurring cancer. Neoplasia 9:960–969
Feng X, Jiang Y, Xie L, Jiang L, Li J et al (2016) Overexpression of proteasomal activator PA28α serves as a prognostic factor in oral squamous cell carcinoma. J Exp Clin Cancer Res 35:35
Chen JY, Xu L, Fang WM, Han JY, Wang K, Zhu KS (2017) Identification of PA28β as a potential novel biomarker in human esophageal squamous cell carcinoma. Tumour Biol 39:1010428317719780
Morozov AV, Karpov VL (2019) Proteasomes and several aspects of their heterogeneity relevant to cancer. Front Oncol 9:761
Cohen S, Nathan JA, Goldberg AL (2015) Muscle wasting in disease: molecular mechanisms and promising therapies. Nat Rev Drug Discov 14:58–74
Mitch WE, Medina R, Grieber S, May RC, England BK et al (1994) Metabolic acidosis stimulates muscle protein degradation by activating the adenosine triphosphate-dependent pathway involving ubiquitin and proteasomes. J Clin Invest 93:2127–2133
Price SR, Bailey JL, Wang X, Jurkovitz C, England BK et al (1996) Muscle wasting in insulinopenic rats results from activation of the ATP-dependent, ubiquitin-proteasome proteolytic pathway by a mechanism including gene transcription. J Clin Invest 98:1703–1708
Lecker SH, Jagoe RT, Gilbert A, Gomes M, Baracos V et al (2004) Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. FASEB J 18:39–51
Lecker SH, Goldberg AL, Mitch WE (2006) Protein degradation by the ubiquitin-proteasome pathway in normal and disease states. J Am Soc Nephrol 17:1807–1819
Langen RCJ, Gosker HR, Remels AHV, Schols AMWJ (2013) Triggers and mechanisms of skeletal muscle wasting in chronic obstructive pulmonary disease. Int J Biochem Cell Biol 45:2245–2256
Saxton RA, Sabatini DM (2017) mTOR signaling in growth, metabolism, and disease. Cell 168:960–976
Zhang Y, Manning BD (2015) mTORC1 signaling activates NRF1 to increase cellular proteasome levels. Cell Cycle 14:2011–2017
Mearini G, Schlossarek S, Willis MS, Carrier L (2008) The ubiquitin-proteasome system in cardiac dysfunction. Biochim Biophys Acta 1782:749–763
Heitmeier T, Sydykov A, Lukas C, Vroom C, Korfei M et al (2020) Altered proteasome function in right ventricular hypertrophy. Cardiovasc Res 116:406–415
Cellerino A, Ori A (2017) What have we learned on aging from omics studies? Semin Cell Dev Biol 70:177–189
López-Otín C, Blasco M, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–1217
Morimoto RI, Cuervo AM (2014) Proteostasis and the aging proteome in health and disease. J Gerontol A Biol Sci Med Sci 69(Suppl 1):S33–S38
Tomaru U, Takahashi S, Ishizu A, Miyatake Y, Gohda A et al (2012) Decreased proteasomal activity causes age-related phenotypes and promotes the development of metabolic abnormalities. Am J Pathol 180:963–972
Mayor T, Sharon M, Glickman MH (2016) Tuning the proteasome to brighten the end of the journey. Am J Physiol Cell Physiol 311:C793–C804
Gavilán MP, Castaño A, Torres M, Portavella M, Caballero C et al (2009) Age-related increase in the immunoproteasome content in rat hippocampus: molecular and functional aspects. J Neurochem 108:260–272
Ferrington DA, Husom AD, Thompson LV (2005) Altered proteasome structure, function, and oxidation in aged muscle. FASEB J 19:644–646
Caniard A, Ballweg K, Lukas C, Yildirim AÖ, Eickelberg O, Meiners S (2015) Proteasome function is not impaired in healthy aging of the lung. Aging 7:776–792
Pickering AM, Lehr M, Miller RA (2015) Lifespan of mice and primates correlates with immunoproteasome expression. J Clin Invest 125:2059–2068
Chondrogianni N, Georgila K, Kourtis N, Tavernarakis N, Gonos ES (2015) 20S proteasome activation promotes life span extension and resistance to proteotoxicity in Caenorhabditis elegans. FASEB J 29:611–622
Nguyen NN, Rana A, Goldman C, Moore R, Tai J et al (2019) Proteasome β5 subunit overexpression improves proteostasis during aging and extends lifespan in Drosophila melanogaster. Sci Rep 9:3170
Rodriguez KA, Edrey YH, Osmulski P, Gaczynska M, Buffenstein R (2012) Altered composition of liver proteasome assemblies contributes to enhanced proteasome activity in the exceptionally long-lived naked mole-rat. PloS One 7:e35890
Chondrogianni N, Petropoulos I, Franceschi C, Friguet B, Gonos ES (2000) Fibroblast cultures from healthy centenarians have an active proteasome. Exp Gerontol 35:721–728
Chondrogianni N, Sakellari M, Lefaki M, Papaevgeniou N, Gonos ES (2014) Proteasome activation delays aging in vitro and in vivo. Free Radic Biol Med 71:303–320
Daniele S, Giacomelli C, Martini C (2018) Brain ageing and neurodegenerative disease: the role of cellular waste management. Biochem Pharmacol 158:207–216
Ross CA, Poirier MA (2005) Opinion: what is the role of protein aggregation in neurodegeneration? Nat Rev Mol Cell Biol 6:891–898
Boland B, Yu WH, Corti O, Mollereau B, Henriques A et al (2018) Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing. Nat Rev Drug Discov 17:660–688
Ciechanover A, Brundin P (2003) The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg. Neuron 40:427–446
Paine SML, Anderson G, Bedford K, Lawler K, Mayer RJ, Lowe J, Bedford L (2013) Pale body-like inclusion formation and neurodegeneration following depletion of 26S proteasomes in mouse brain neurones are independent of α-synuclein. PloS One 8:e54711
Myeku N, Clelland CL, Emrani S, Kukushkin NV, Yu WH, Goldberg AL, Duff KE (2016) Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling. Nat Med 22:46–53
Limanaqi F, Biagioni F, Gaglione A, Busceti CL, Fornai F (2019) A sentinel in the crosstalk between the nervous and immune system: the (immuno)-proteasome. Front Immunol 10:628
Waelter S, Boeddrich A, Lurz R, Scherzinger E, Lueder G, Lehrach H, Wanker EE (2001) Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation. Mol Biol Cell 12:1393–1407
Wanderer J, Morton AJ (2007) Differential morphology and composition of inclusions in the R6/2 mouse and PC12 cell models of Huntington’s disease. Histochem Cell Biol 127:473–484
Seo H, Sonntag KC, Kim W, Cattaneo E, Isacson O (2007) Proteasome activator enhances survival of Huntington’s disease neuronal model cells. PLoS One 2:e238
Jeon J, Kim W, Jang J, Isacson O, Seo H (2016) Gene therapy by proteasome activator, PA28γ, improves motor coordination and proteasome function in Huntington’s disease YAC128 mice. Neuroscience 324:20–28
Bett JS, Goellner GM, Woodman B, Pratt G, Rechsteiner M, Bates GP (2006) Proteasome impairment does not contribute to pathogenesis in R6/2 Huntington’s disease mice: exclusion of proteasome activator REGgamma as a therapeutic target. Hum Mol Genet 15:33–44
McNaught KSP, Jnobaptiste R, Jackson T, Jengelley TA (2010) The pattern of neuronal loss and survival may reflect differential expression of proteasome activators in Parkinson’s disease. Synapse 64:241–250
Drews O, Taegtmeyer H (2014) Targeting the ubiquitin-proteasome system in heart disease: the basis for new therapeutic strategies. Antioxid Redox Signal 21:2322–2343
Drews O (2014) The left and right ventricle in the grip of protein degradation: similarities and unique patterns in regulation. J Mol Cell Cardiol 72:52–55
Zong C, Gomes AV, Drews O, Li X, Young GW et al (2006) Regulation of murine cardiac 20S proteasomes: role of associating partners. Circ Res 99:372–380
Ranek MJ, Zheng H, Huang W, Kumarapeli AR, Li J, Liu J, Wang X (2015) Genetically induced moderate inhibition of 20S proteasomes in cardiomyocytes facilitates heart failure in mice during systolic overload. J Mol Cell Cardiol 85:273–281
Chen Q, Liu JB, Horak KM, Zheng H, Kumarapeli ARK et al (2005) Intrasarcoplasmic amyloidosis impairs proteolytic function of proteasomes in cardiomyocytes by compromising substrate uptake. Circ Res 97:1018–1026
Xie X, Bi HL, Lai S, Zhang YL, Li N et al (2019) The immunoproteasome catalytic β5i subunit regulates cardiac hypertrophy by targeting the autophagy protein ATG5 for degradation. Sci Adv 5:eaau0495
Li J, Wang S, Zhang YL, Bai J, Lin QY et al (2019) Immunoproteasome subunit β5i promotes Ang II (angiotensin II)-induced atrial fibrillation by targeting ATRAP (Ang II type I receptor-associated protein) degradation in mice. Hypertension 73:92–101
Beling A, Kespohl M (2018) Proteasomal protein degradation: adaptation of cellular proteolysis with impact on virus-and cytokine-mediated damage of heart tissue during myocarditis. Front Immunol 9:2620
Wilck N, Ludwig A (2014) Targeting the ubiquitin-proteasome system in atherosclerosis: status quo, challenges, and perspectives. Antioxid Redox Signal 21:2344–2363
Hewing B, Ludwig A, Dan C, Pötzsch M, Hannemann C et al (2017) Immunoproteasome subunit ß5i/LMP7-deficiency in atherosclerosis. Sci Rep 7:13342
Li J, Horak KM, Su H, Sanbe A, Robbins J, Wang X (2011) Enhancement of proteasomal function protects against cardiac proteinopathy and ischemia/reperfusion injury in mice. J Clin Invest 121:3689–3700
Mulugeta S, Nguyen V, Russo SJ, Muniswamy M, Beers MF (2005) A surfactant protein C precursor protein BRICHOS domain mutation causes endoplasmic reticulum stress, proteasome dysfunction, and caspase 3 activation. Am J Respir Cell Mol Biol 32:521–530
Somborac-Bacura A, van der Toorn M, Franciosi L, Slebos DJ, Zanic-Grubisic T, Bischoff R, van Oosterhout AJM (2013) Cigarette smoke induces endoplasmic reticulum stress response and proteasomal dysfunction in human alveolar epithelial cells. Exp Physiol 98:316–325
Yamada Y, Tomaru U, Ishizu A, Ito T, Kiuchi T et al (2015) Decreased proteasomal function accelerates cigarette smoke-induced pulmonary emphysema in mice. Lab Invest 95:625–634
Sixt SU, Beiderlinden M, Jennissen HP, Peters J (2007) Extracellular proteasome in the human alveolar space: a new housekeeping enzyme? Am J Physiol Lung Cell Mol Physiol 292:L1280–L1288
Sixt SU, Dahlmann B (2008) Extracellular, circulating proteasomes and ubiquitin—incidence and relevance. Biochim Biophys Acta 1782:817–823
Sixt SU, Alami R, Hakenbeck J, Adamzik M, Kloss A et al (2012) Distinct proteasome subpopulations in the alveolar space of patients with the acute respiratory distress syndrome. Mediat Inflamm 2012:204250
Dieudé M, Bell C, Turgeon J, Beillevaire D, Pomerleau L et al (2015) The 20S proteasome core, active within apoptotic exosome-like vesicles, induces autoantibody production and accelerates rejection. Sci Transl Med 7:318ra200
Shi J, Liu X, Xu C, Ge J, Ren J et al (2015) Up-regulation of PSMB4 is associated with neuronal apoptosis after neuroinflammation induced by lipopolysaccharide. J Mol Histol 46:457–466
Wei W, Zou Y, Jiang Q, Zhou Z, Ding H, Yan L, Yang S (2017) PSMB5 is associated with proliferation and drug resistance in triple-negative breast cancer. Int J Biol Markers 33:102–108
Zhang X, Lin D, Lin Y, Chen H, Zou M et al (2017) Proteasome beta-4 subunit contributes to the development of melanoma and is regulated by miR-148b. Tumour Biol 39:1010428317705767
Li H, Zhang J, Zhen C, Yang B, Feng L (2018) Gankyrin as a potential target for tumor therapy: evidence and perspectives. Am J Transl Res 10:1949–1960
de Bettignies G, Coux O (2010) Proteasome inhibitors: dozens of molecules and still counting. Biochimie 92:1530–1545
Beck P, Dubiella C, Groll M (2012) Covalent and non-covalent reversible proteasome inhibition. Biol Chem 393:1101–1120
Thibaudeau TA, Smith DM (2019) A practical review of proteasome pharmacology. Pharmacol Rev 71:170–197
Kisselev AF, van der Linden WA, Overkleeft HS (2012) Proteasome inhibitors: an expanding army attacking a unique target. Chem Biol 19:99–115
Screen M, Britton M, Downey SL, Verdoes M, Voges MJ et al (2010) Nature of pharmacophore influences active site specificity of proteasome inhibitors. J Biol Chem 285:40125–40134
Verdoes M, Florea BI, Menendez-Benito V, Maynard CJ, Witte MD et al (2006) A fluorescent broad-spectrum proteasome inhibitor for labeling proteasomes in vitro and in vivo. Chem Biol 13:1217–1226
Gan J, Leestemaker Y, Sapmaz A, Ovaa H (2019) Highlighting the proteasome: using fluorescence to visualize proteasome activity and distribution. Front Mol Biosci 6:14
Teicher BA, Tomaszewski JE (2015) Proteasome inhibitors. Biochem Pharmacol 96:1–9
Park JE, Miller Z, Jun Y, Lee W, Kim KB (2018) Next-generation proteasome inhibitors for cancer therapy. Transl Res 198:1–16
Herndon TM, Deisseroth A, Kaminskas E, Kane RC, Koti KM et al (2013) U.S. Food and Drug Administration approval: carfilzomib for the treatment of multiple myeloma. Clin Cancer Res 19:4559–4563
Kisselev AF, Callard A, Goldberg AL (2006) Importance of the different proteolytic sites of the proteasome and the efficacy of inhibitors varies with the protein substrate. J Biol Chem 281:8582–8590
Cromm PM, Crews CM (2017) The proteasome in modern drug discovery: second life of a highly valuable drug target. ACS Cent Sci 3:830–838
Basler M, Mundt S, Bitzer A, Schmidt C, Groettrup M (2015) The immunoproteasome: a novel drug target for autoimmune diseases. Clin Exp Rheumatol 33:74–79
Kammerl IE, Meiners S (2016) Proteasome function shapes innate and adaptive immune responses. Am J Physiol Lung Cell Mol Physiol 311:L328–L336
Eskandari SK, Seelen MAJ, Lin G, Azzi JR (2017) The immunoproteasome: an old player with a novel and emerging role in alloimmunity. Am J Transplant 17:3033–3039
Sula Karreci E, Fan H, Uehara M, Mihali AB, Singh PK et al (2016) Brief treatment with a highly selective immunoproteasome inhibitor promotes long-term cardiac allograft acceptance in mice. Proc Natl Acad Sci USA 113:E8425–E8432
Basler M, Maurits E, de Bruin G, Koerner J, Overkleeft HS, Groettrup M (2018) Amelioration of autoimmunity with an inhibitor selectively targeting all active centres of the immunoproteasome. Br J Pharmacol 175:38–52
Bibo-Verdugo B, Jiang Z, Caffrey CR, O’Donoghue AJ (2017) Targeting proteasomes in infectious organisms to combat disease. FEBS J 284:1503–1517
Lin G, Li D, de Carvalho LPS, Deng H, Tao H et al (2009) Inhibitors selective for mycobacterial versus human proteasomes. Nature 461:624–626
Lin G, Chidawanyika T, Tsu C, Warrier T, Vaubourgeix J et al (2013) N,C-Capped dipeptides with selectivity for mycobacterial proteasome over human proteasomes: role of S3 and S1 binding pockets. J Am Chem Soc 135:9968–9971
Totaro KA, Barthelme D, Simpson PT, Jiang X, Lin G et al (2017) Rational design of selective and bioactive inhibitors of the Mycobacterium tuberculosis proteasome. ACS Infect Dis 3:176–181
Li H, O’Donoghue AJ, van der Linden WA, Xie SC, Yoo E et al (2016) Structure- and function-based design of Plasmodium-selective proteasome inhibitors. Nature 530:233–236
Kirkman LA, Zhan W, Visone J, Dziedziech A, Singh PK et al (2018) Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance. Proc Natl Acad Sci USA 115:E6863–E6870
Khare S, Nagle AS, Biggart A, Lai YH, Liang F et al (2016) Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness. Nature 537:229–233
Robak P, Robak T (2019) Bortezomib for the treatment of hematologic malignancies: 15 years later. Drugs RD 19:73–92
Kaplan GS, Torcun CC, Grune T, Ozer NK, Karademir B (2017) Proteasome inhibitors in cancer therapy: treatment regimen and peripheral neuropathy as a side effect. Free Radic Biol Med 103:1–13
Mohan M, Matin A, Davies FE (2017) Update on the optimal use of bortezomib in the treatment of multiple myeloma. Cancer Manag Res 9:51–63
Cole DC, Frishman WH (2018) Cardiovascular complications of proteasome inhibitors used in multiple myeloma. Cardiol Rev 26:122–129
Wallington-Beddoe CT, Sobieraj-Teague M, Kuss BJ, Pitson SM (2018) Resistance to proteasome inhibitors and other targeted therapies in myeloma. Br J Haematol 182:11–28
Robak P, Drozdz I, Szemraj J, Robak T (2018) Drug resistance in multiple myeloma. Cancer Treat Rev 70:199–208
Oerlemans R, Franke NE, Assaraf YG, Cloos J, van Zantwijk I et al (2008) Molecular basis of bortezomib resistance: proteasome subunit beta5 (PSMB5) gene mutation and overexpression of PSMB5 protein. Blood 112:2489–2499
Li B, Fu J, Chen P, Ge X, Li Y et al (2015) The nuclear factor (erythroid-derived 2)-like 2 and proteasome maturation protein axis mediates bortezomib resistance in multiple myeloma. J Biol Chem 290:29854–29868
Njomen E, Osmulski PA, Jones CL, Gaczynska M, Tepe JJ (2018) Small molecule modulation of proteasome assembly. Biochemistry 57:4214–4224
Trader DJ, Simanski S, Dickson P, Kodadek T (2017) Establishment of a suite of assays that support the discovery of proteasome stimulators. Biochim Biophys Acta Gen Subj 1861:892–899
Jones CL, Njomen E, Sjögren B, Dexheimer TS, Tepe JJ (2017) Small molecule enhancement of 20S proteasome activity targets intrinsically disordered proteins. ACS Chem Biol 12:2240–2247
Coleman R, Trader DJ (2018) Development and application of a sensitive peptide reporter to discover 20S proteasome stimulators. ACS Comb Sci 20:269–276
Leestemaker Y, de Jong A, Witting KF, Penning R, Schuurman K et al (2017) Proteasome activation by small molecules. Cell Chem Biol 24:725–736.e7
Wedel S, Manola M, Cavinato M, Trougakos IP, Jansen-Dürr P (2018) Targeting protein quality control mechanisms by natural products to promote healthy ageing. Molecules 23:E1219
Athanasopoulou S, Chondrogianni N, Santoro A, Asimaki K, Delitsikou V et al (2018) Beneficial effects of elderly tailored Mediterranean diet on the proteasomal proteolysis. Front Physiol 9:457
Inobe T, Genmei R (2015) Inhibition of the 26S proteasome by peptide mimics of the coiled-coil region of its ATPase subunits. Biochem Biophys Res Commun 468:143–150
Acknowledgments
The authors wish to thank Prof. Elke Krüger (Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald, Germany) for her critical reading of the manuscript and helpful comments. They also acknowledge the support of the COST program, Action Proteostasis BM1307.
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Coux, O., Zieba, B.A., Meiners, S. (2020). The Proteasome System in Health and Disease. In: Barrio, R., Sutherland, J., Rodriguez, M. (eds) Proteostasis and Disease . Advances in Experimental Medicine and Biology, vol 1233. Springer, Cham. https://doi.org/10.1007/978-3-030-38266-7_3
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