Proteasomes in Autoinflammation

  • Anja Brehm
  • Frédéric Ebstein
  • Elke KrügerEmail author


The cellular proteostasis network integrates all signals controlling protein synthesis, folding, trafficking, and clearance machineries in multiple subcellular compartments to maintain the integrity of the proteome and to ensure the survival of cells and tissues under varying proteotoxic insults. We here review the proteostasis network that controls the adaptation of the ubiquitin proteasome system (UPS) to cellular demands and its perturbations in autoinflammation. Proteotoxic stress of various physiological origins such as inflammation can be typically counteracted by the shut-down of global protein translation, or the up-regulation of protein quality control and degradation machineries including stress specific sets of ubiquitin-conjugation and deconjugation factors as well as alternative proteasome isoforms. The loss of controlled adaptation and/or impairment of proteasome function represent a hallmark of various proteinopathies including proteasome associated autoinflammatory syndromes (PRAAS) , which are accompanied by oxidative stress and induction of endoplasmic reticulum (ER) stress. A common and surprising feature of such diseases is the initiation of chronic inflammation under pathogen-free conditions through the release of various mediators, particularly type I interferon (IFN). Recent work in this field has highlighted a possible role of ER-membrane located signaling cascades originating from TCF11/Nrf1 as well as the PERK and IRE1α arms of the unfolded protein response (UPR) in this process. Their precise implication in the pathogenesis of proteinopathies as well as their relevance for the design of novel drug targets will be discussed.


Proteostasis Ubiquitin Proteasome Inflammation Unfolded protein response Proteinopathy Interferonopathy PRAAS 



Aggresome-like induced structures


Antioxidant response elements


Activated transcription factor


Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature


C/EBP-homologous protein 10




Core particle


Dendritic aggresome-like induced structures


Dendritic cell


DNA damage-inducible protein homolog 2


Defective ribosomal product


Deubiquitinating enzyme


eukaryotic translation initiation factor 2


Endoplasmic reticulum


ER-associated degradation


Growth arrest and DNA damage-inducible protein 34






Inositol-requiring protein 1


Interferon regulatory factor 3


Interferon-stimulated gene


Joint contractures muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy


Keratosis linearis with ichthyosis congenita and sclerosing keratoderma syndrome


Major histocompatibility complex


NADPH oxidase


Nakajo-Nishimura syndrome


Nuclear factor erythroid 2-related factor 1


2′-5′-Oligoadenylate synthase-like protein


Proteasome activator 200


Proteasome activator 28


Proteasome assembly chaperone


Pathogen-associated molecular pattern


Protein kinase R-like endoplasmic reticulum kinase


Protein kinase R


Proteasome maturation protein


Proteasome-associated autoinflammatory syndrome


Pathogen recognition receptor


IRE1α-dependent decay


Retinoic acid-inducible gene 1 protein


Reactive-nitrogen species


Reactive oxygen species


Regulatory particle


Regulatory particle non-ATPase subunit


Standard proteasome


Transcription factor 11


Unfolded protein response


Ubiquitin-proteasome system


X-box-binding protein 1


Xanthine oxidase



This work was supported by the German Research Foundation and the Fritz-Thyssen-Foundation.


  1. 1.
    Labbadia J, Morimoto RI. The biology of proteostasis in aging and disease. Annu Rev Biochem. 2015;84:435–64.CrossRefGoogle Scholar
  2. 2.
    Kaushik S, Cuervo AM. Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol. 2012;22:407–17.CrossRefGoogle Scholar
  3. 3.
    Yerbury JJ, Ooi L, Dillin A, et al. Walking the tightrope: proteostasis and neurodegenerative disease. J Neurochem. 2016;137:489–505.CrossRefGoogle Scholar
  4. 4.
    Dikic I. Proteasomal and autophagic degradation systems. Annu Rev Biochem. 2017;86:193–224.CrossRefGoogle Scholar
  5. 5.
    Dammer EB, Na CH, Xu P, et al. Polyubiquitin linkage profiles in three models of proteolytic stress suggest the etiology of Alzheimer disease. J Biol Chem. 2011;286:10457–65.CrossRefGoogle Scholar
  6. 6.
    Mevissen TET, Komander D. Mechanisms of deubiquitinase specificity and regulation. Annu Rev Biochem. 2017;86:159–92.CrossRefGoogle Scholar
  7. 7.
    Budenholzer L, Cheng CL, Li Y, Hochstrasser M. Proteasome structure and assembly. J Mol Biol. 2017;429(22):3500–24; S0022-2836:30270-X.CrossRefGoogle Scholar
  8. 8.
    Shi Y, Chen X, Elsasser S, et al. Rpn1 provides adjacent receptor sites for substrate binding and deubiquitination by the proteasome. Science. 2016;351(6275). pii: aad9421.Google Scholar
  9. 9.
    Brehm A, Krüger E. Dysfunction in protein clearance by the proteasome: impact on autoinflammatory diseases. Semin Immunopathol. 2015;37:323–33.CrossRefGoogle Scholar
  10. 10.
    Sahara K, Kogleck L, Yashiroda H, Murata S. The mechanism for molecular assembly of the proteasome. Adv Biol Regul. 2014;54:51–8.CrossRefGoogle Scholar
  11. 11.
    Vigneron N, Van den Eynde BJ. Proteasome subtypes and regulators in the processing of antigenic peptides presented by class I molecules of the major histocompatibility complex. Biomol Ther. 2014;4:994–1025.Google Scholar
  12. 12.
    Huang L, Haratake K, Miyahara H, Chiba T. Proteasome activators, PA28γ and PA200, play indispensable roles in male fertility. Sci Rep. 2016;6:23171.CrossRefGoogle Scholar
  13. 13.
    Antón LC, Yewdell JW. Translating DRiPs: MHC class I immunosurveillance of pathogens and tumors. J Leukoc Biol. 2014;95:551–62.CrossRefGoogle Scholar
  14. 14.
    Lelouard H, Gatti E, Cappello F, Gresser O, Camosseto V, Pierre P. Transient aggregation of ubiquitinated proteins during dendritic cell maturation. Nature. 2002;417:177–82.CrossRefGoogle Scholar
  15. 15.
    Canadien V, Tan T, Zilber R, Szeto J, Perrin AJ, Brumell JH. Cutting edge: microbial products elicit formation of dendritic cell aggresome-like induced structures in macrophages. J Immunol. 2005;174:2471–5.CrossRefGoogle Scholar
  16. 16.
    Seifert UL, Bialy P, Ebstein F, et al. Immunoproteasomes preserve protein homeostasis upon interferon-induced oxidative stress. Cell. 2010;142:613–24.CrossRefGoogle Scholar
  17. 17.
    Opitz E, Koch A, Klingel K, et al. Impairment of immunoproteasome function by beta5i/LMP7 subunit deficiency results in severe enterovirus myocarditis. PLoS Pathog. 2011;7:e1002233.CrossRefGoogle Scholar
  18. 18.
    Pickering AM, Koop AL, Teoh CY, Ermak G, Grune T, Davies KJ. The immunoproteasome, the 20S proteasome and the PA28alphabeta proteasome regulator are oxidative-stress-adaptive proteolytic complexes. Biochem J. 2010;432:585–94.CrossRefGoogle Scholar
  19. 19.
    Li J, Powell SR, Wang X. Enhancement of proteasome function by PA28alpha; overexpression protects against oxidative stress. FASEB J. 2011;25:883–93.CrossRefGoogle Scholar
  20. 20.
    Martin I, Dawson VL, Dawson TM. Recent advances in the genetics of Parkinson’s disease. Annu Rev Genomics Hum Genet. 2011;12:301–25.CrossRefGoogle Scholar
  21. 21.
    Uversky VN. Neuropathology, biochemistry, and biophysics of alpha-synuclein aggregation. J Neurochem. 2007;103:17–37.PubMedGoogle Scholar
  22. 22.
    Dahlqvist J, Klar J, Tiwari N, et al. 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. 2010;86:596–603.CrossRefGoogle Scholar
  23. 23.
    Agarwal AK, Xing C, DeMartino GN, et al. PSMB8 encoding the beta5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome. Am J Hum Genet. 2010;87:866–72.CrossRefGoogle Scholar
  24. 24.
    Kitamura A, Maekawa Y, Uehara H, et al. A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humans. J Clin Invest. 2011;121:4150–60.CrossRefGoogle Scholar
  25. 25.
    Arima K, Kinoshita A, Mishima H, et al. Proteasome assembly defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo-Nishimura syndrome. Proc Natl Acad Sci U S A. 2011;108:14914–9.CrossRefGoogle Scholar
  26. 26.
    Kunimoto K, Kimura A, Uede K, et al. A new infant case of Nakajo-Nishimura syndrome with a genetic mutation in the immunoproteasome subunit: an overlapping entity with JMP and CANDLE syndrome related to PSMB8 mutations. Dermatology. 2013;227:26–30.CrossRefGoogle Scholar
  27. 27.
    Brehm A, Liu Y, Sheikh A, et al. Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production. J Clin Invest. 2015;125:4196–211.CrossRefGoogle Scholar
  28. 28.
    Liu Y, Ramot Y, Torrelo A, et al. Mutations in proteasome subunit beta type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity. Arthritis Rheum. 2012;64:895–907.CrossRefGoogle Scholar
  29. 29.
    Cavalcante MP, Brunelli JB, Miranda CC, et al. CANDLE syndrome: chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature-a rare case with a novel mutation. Eur J Pediatr. 2016;175:735–40.CrossRefGoogle Scholar
  30. 30.
    Wahl C, Kautzmann S, Krebiehl G, et al. A comprehensive genetic study of the proteasomal subunit S6 ATPase in German Parkinson’s disease patients. J Neural Transm (Vienna). 2008;115:1141–8.CrossRefGoogle Scholar
  31. 31.
    Küry S, Besnard T, Ebstein F, et al. De novo disruption of the proteasome regulatory subunit PSMD12 causes a syndromic neurodevelopmental disorder. Am J Hum Genet. 2017;100:352–63.CrossRefGoogle Scholar
  32. 32.
    Hipp MS, Park SH, Hartl FU. Proteostasis impairment in protein-misfolding and -aggregation diseases. Trends Cell Biol. 2014;24:506–14.CrossRefGoogle Scholar
  33. 33.
    Ebstein F, Kloetzel PM, Krüger E, Seifert U. Emerging roles of immunoproteasomes beyond MHC class I antigen processing. Cell Mol Life Sci. 2012;69:2543–58.CrossRefGoogle Scholar
  34. 34.
    Wojcik S. Crosstalk between autophagy and proteasome protein degradation systems: possible implications for cancer therapy. Folia Histochem Cytobiol. 2013;51:249–64.CrossRefGoogle Scholar
  35. 35.
    Zhang Y, Nicholatos J, Dreier JR, et al. Coordinated regulation of protein synthesis and degradation by mTORC1. Nature. 2014;513:440–3.CrossRefGoogle Scholar
  36. 36.
    Hetz C, Chevet E, Oakes SA. Proteostasis control by the unfolded protein response. Nat Cell Biol. 2015;17:829–38.CrossRefGoogle Scholar
  37. 37.
    Grootjans J, Kaser A, Kaufman RJ, Blumberg RS. The unfolded protein response in immunity and inflammation. Nat Rev Immunol. 2016;16:469–84.CrossRefGoogle Scholar
  38. 38.
    Steffen J, Seeger M, Koch A, Krüger E. Proteasomal degradation is transcriptionally controlled by TCF11 via an ERAD-dependent feedback loop. Mol Cell. 2010;40:147–58.CrossRefGoogle Scholar
  39. 39.
    Radhakrishnan SK, Lee CS, Young P, Beskow A, Chan JY, Deshaies RJ. Transcription factor Nrf1 mediates the proteasome recovery pathway after proteasome inhibition in mammalian cells. Mol Cell. 2010;38:17–28.CrossRefGoogle Scholar
  40. 40.
    Koch A, Steffen J, Krüger E. TCF11 at the crossroads of oxidative stress and the ubiquitin proteasome system. Cell Cycle. 2011;10:1200–7.CrossRefGoogle Scholar
  41. 41.
    Radhakrishnan SK, den Besten W, Deshaies RJ. p97-dependent retrotranslocation and proteolytic processing govern formation of active Nrf1 upon proteasome inhibition. Elife. 2014;3:e01856.CrossRefGoogle Scholar
  42. 42.
    Sotzny F, Schormann E, Kühlewindt I, et al. TCF11/Nrf1-mediated induction of proteasome expression prevents cytotoxicity by rotenone. Antioxid Redox Signal. 2016;25:870–85.CrossRefGoogle Scholar
  43. 43.
    Vangala JR, Sotzny F, Krüger E, Deshaies RJ, Radhakrishnan SK. Nrf1 can be processed and activated in a proteasome-independent manner. Curr Biol. 2016;26:R834–5.CrossRefGoogle Scholar
  44. 44.
    Lencer WI, DeLuca H, Grey MJ, Cho JA. Innate immunity at mucosal surfaces: the IRE1-RIDD-RIG-I pathway. Trends Immunol. 2015;36:401–9.CrossRefGoogle Scholar
  45. 45.
    Heaton SM, Borg NA, Dixit VM. Ubiquitin in the activation and attenuation of innate antiviral immunity. J Exp Med. 2016;213:1–13.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Institut für BiochemieCharité Universitätsmedizin BerlinBerlinGermany
  2. 2.Institut für Medizinische Biochemie und MolekularbiologieUniversitätsmedizin GreifswaldGreifswaldGermany

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