Skip to main content
SpringerLink
Log in
SpringerLink
Log in

Immunoproteasome System in Aging, Lifespan, and Age-Associated Disease

  • Living reference work entry
  • First Online:
Handbook of Immunosenescence

Abstract

The immunoproteasome system is an inducible alternative form of the proteasome in which certain subunits have been replaced by immunoproteaosme-specific variants. The immunoproteasome has roles in the generation of peptides for MHC class I antigen presentation and in clearance of oxidized proteins. It has a protective role against various cancers. It has also been described as being induced in a range of neurodegenerative diseases, although it is unclear whether in these diseases its effects are protective or pathogenic. In addition, the immunoproteasome has recently been shown to be upregulated in many long-lived species and in slow-aging animal models, leading to interest in this protein as a regulator of aging and age-associated disease. It remains unclear whether selection for its upregulation in long-lived species is driven by its roles in proteostasis or resistance to infectious diseases and cancers.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

References

  • Almeida CG, Takahashi RH et al (2006) Beta-amyloid accumulation impairs multivesicular body sorting by inhibiting the ubiquitin-proteasome system. J Neurosci 26(16):4277–4288

    Article  CAS  PubMed  Google Scholar 

  • Andersson M, Sjostrand J et al (2000) Caspase and proteasome activity during staurosporin-induced apoptosis in lens epithelial cells. Invest Ophthalmol Vis Sci 41(9):2623–2632

    CAS  PubMed  Google Scholar 

  • Bonizzi G, Karin M (2004) The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25(6):280–288

    Article  CAS  PubMed  Google Scholar 

  • Brooks P, Fuertes G et al (2000a) Subcellular localization of proteasomes and their regulatory complexes in mammalian cells. Biochem J 346(Pt 1):155–161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brooks P, Murray RZ et al (2000b) Association of immunoproteasomes with the endoplasmic reticulum. Biochem J 352(Pt 3):611–615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bubenik J (2004) MHC class I down-regulation: tumour escape from immune surveillance? (review). Int J Oncol 25(2):487–491

    CAS  PubMed  Google Scholar 

  • Buffenstein R (2008) Negligible senescence in the longest living rodent, the naked mole-rat: insights from a successfully aging species. J Comp Physiol B 178(4):439–445

    Article  PubMed  Google Scholar 

  • Bulteau AL, Petropoulos I et al (2000) Age-related alterations of proteasome structure and function in aging epidermis. Exp Gerontol 35(6–7):767–777

    Article  CAS  PubMed  Google Scholar 

  • Caballero M, Liton PB et al (2004) Effects of donor age on proteasome activity and senescence in trabecular meshwork cells. Biochem Biophys Res Commun 323(3):1048–1054

    Article  CAS  PubMed  Google Scholar 

  • Carrard G, Bulteau AL et al (2002) Impairment of proteasome structure and function in aging. Int J Biochem Cell Biol 34(11):1461–1474

    Article  CAS  PubMed  Google Scholar 

  • Carrard G, Dieu M et al (2003) Impact of ageing on proteasome structure and function in human lymphocytes. Int J Biochem Cell Biol 35(5):728–739

    Article  CAS  PubMed  Google Scholar 

  • Chondrogianni N, Petropoulos I et al (2000) Fibroblast cultures from healthy centenarians have an active proteasome. Exp Gerontol 35(6–7):721–728

    Article  CAS  PubMed  Google Scholar 

  • Chondrogianni N, Stratford FL et al (2003) Central role of the proteasome in senescence and survival of human fibroblasts: induction of a senescence-like phenotype upon its inhibition and resistance to stress upon its activation. J Biol Chem 278(30):28026–28037

    Article  CAS  PubMed  Google Scholar 

  • Chondrogianni N, Tzavelas C et al (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(12):11840–11850

    Article  CAS  PubMed  Google Scholar 

  • Ciechanover A (1994) The ubiquitin-proteasome proteolytic pathway. Cell 79(1):13–21

    Article  CAS  PubMed  Google Scholar 

  • Davies KJ (2001) Degradation of oxidized proteins by the 20S proteasome. Biochimie 83(3–4):301–310

    Article  CAS  PubMed  Google Scholar 

  • Delic J, Masdehors P et al (1998) The proteasome inhibitor lactacystin induces apoptosis and sensitizes chemo- and radioresistant human chronic lymphocytic leukaemia lymphocytes to TNF-alpha-initiated apoptosis. Br J Cancer 77(7):1103–1107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Diaz-Hernandez M, Hernandez F et al (2003) Neuronal induction of the immunoproteasome in Huntington’s disease. J Neurosci 23(37):11653–11661

    CAS  PubMed  Google Scholar 

  • Dissemond J, Goette P et al (2003) Immunoproteasome subunits LMP2 and LMP7 downregulation in primary malignant melanoma lesions: association with lack of spontaneous regression. Melanoma Res 13(4):371–377

    Article  CAS  PubMed  Google Scholar 

  • Dominick G, Berryman DE et al (2015) Regulation of mTOR activity in Snell dwarf and GH receptor gene-disrupted mice. Endocrinology 156(2):565–575

    Article  PubMed  Google Scholar 

  • Dozmorov I, Galecki A et al (2002) Gene expression profile of long-lived snell dwarf mice. J Gerontol A Biol Sci Med Sci 57(3):B99–108

    Article  PubMed  Google Scholar 

  • Esteban F, Concha A et al (1990) Lack of MHC class I antigens and tumour aggressiveness of the squamous cell carcinoma of the larynx. Br J Cancer 62(6):1047–1051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fehling HJ, Swat W et al (1994) MHC class I expression in mice lacking the proteasome subunit LMP-7. Science 265(5176):1234–1237

    Article  CAS  PubMed  Google Scholar 

  • Fellerhoff B, Gu S et al (2011) The LMP7-K allele of the immunoproteasome exhibits reduced transcript stability and predicts high risk of colon cancer. Cancer Res 71(23):7145–7154

    Article  CAS  PubMed  Google Scholar 

  • Ferrington DA, Husom AD et al (2005) Altered proteasome structure, function, and oxidation in aged muscle. FASEB J 19(6):644–646

    CAS  PubMed  Google Scholar 

  • Fox HS, Bond BL et al (1991) Estrogen regulates the IFN-gamma promoter. J Immunol 146(12):4362–4367

    CAS  PubMed  Google Scholar 

  • Goldberg AL, Rock KL (1992) Proteolysis, proteasomes and antigen presentation. Nature 357(6377):375–379

    Article  CAS  PubMed  Google Scholar 

  • Griffin TA, Nandi D et al (1998) Immunoproteasome assembly: cooperative incorporation of interferon gamma (IFN-gamma)-inducible subunits. J Exp Med 187(1):97–104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grune T, Botzen D et al (2010) Tau protein degradation is catalyzed by the ATP/ubiquitin-independent 20S proteasome under normal cell conditions. Arch Biochem Biophys 500(2):181–188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haeffner A, Thieblemont N et al (1997) Inhibitory effect of growth hormone on TNF-alpha secretion and nuclear factor-kappaB translocation in lipopolysaccharide-stimulated human monocytes. J Immunol 158(3):1310–1314

    CAS  PubMed  Google Scholar 

  • Harrison DE, Strong R et al (2014) Acarbose, 17-alpha-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males. Aging Cell 13(2):273–282

    Article  CAS  PubMed  Google Scholar 

  • Hayashi T, Horiuchi A et al (2011) Molecular approach to uterine Leiomyosarcoma: LMP2-deficient mice as an animal model of spontaneous uterine Leiomyosarcoma. Sarcoma 2011:476498

    Article  PubMed  PubMed Central  Google Scholar 

  • Heink S, Fricke B et al (2006) Tumor cell lines expressing the proteasome subunit isoform LMP7E1 exhibit immunoproteasome deficiency. Cancer Res 66(2):649–652

    Article  CAS  PubMed  Google Scholar 

  • Ho YK, Bargagna-Mohan P et al (2007) LMP2-specific inhibitors: chemical genetic tools for proteasome biology. Chem Biol 14(4):419–430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hong L, Huang HC et al (2014) Relationship between amyloid-beta and the ubiquitin-proteasome system in Alzheimer’s disease. Neurol Res 36(3):276–282

    Article  CAS  PubMed  Google Scholar 

  • Husom AD, Peters EA et al (2004) Altered proteasome function and subunit composition in aged muscle. Arch Biochem Biophys 421(1):67–76

    Article  CAS  PubMed  Google Scholar 

  • Hussong SA, Kapphahn RJ et al (2010) Immunoproteasome deficiency alters retinal proteasome’s response to stress. J Neurochem 113(6):1481–1490

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hwang JS, Chang I et al (2007) Age-associated decrease in proteasome content and activities in human dermal fibroblasts: restoration of normal level of proteasome subunits reduces aging markers in fibroblasts from elderly persons. J Gerontol A Biol Sci Med Sci 62(5):490–499

    Article  PubMed  Google Scholar 

  • Keck S, Nitsch R et al (2003) Proteasome inhibition by paired helical filament-tau in brains of patients with Alzheimer’s disease. J Neurochem 85(1):115–122

    Article  CAS  PubMed  Google Scholar 

  • Keller JN, Huang FF et al (2000) Decreased levels of proteasome activity and proteasome expression in aging spinal cord. Neuroscience 98(1):149–156

    Article  CAS  PubMed  Google Scholar 

  • Kincaid EZ, Che JW et al (2012) Mice completely lacking immunoproteasomes show major changes in antigen presentation. Nat Immunol 13(2):129–135

    Article  CAS  Google Scholar 

  • Kisselev AF, Akopian TN et al (1999) The sizes of peptides generated from protein by mammalian 26 and 20 S proteasomes. Implications for understanding the degradative mechanism and antigen presentation. J Biol Chem 274(6):3363–3371

    Article  CAS  PubMed  Google Scholar 

  • Kloetzel PM, Ossendorp F (2004) Proteasome and peptidase function in MHC-class-I-mediated antigen presentation. Curr Opin Immunol 16(1):76–81

    Article  CAS  PubMed  Google Scholar 

  • Korkolopoulou P, Kaklamanis L et al (1996) Loss of antigen-presenting molecules (MHC class I and TAP-1) in lung cancer. Br J Cancer 73(2):148–153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee CK, Allison DB et al (2002) Transcriptional profiles associated with aging and middle age-onset caloric restriction in mouse hearts. Proc Natl Acad Sci U S A 99(23):14988–14993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leiser SF, Miller RA (2010) Nrf2 signaling, a mechanism for cellular stress resistance in long-lived mice. Mol Cell Biol 30(3):871–884

    Article  CAS  PubMed  Google Scholar 

  • Lopez Salon M, Pasquini L et al (2003) Relationship between beta-amyloid degradation and the 26S proteasome in neural cells. Exp Neurol 180(2):131–143

    Article  CAS  PubMed  Google Scholar 

  • Louie JL, Kapphahn RJ et al (2002) Proteasome function and protein oxidation in the aged retina. Exp Eye Res 75(3):271–284

    Article  CAS  PubMed  Google Scholar 

  • Miller RA, Harrison DE et al (2011) Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci 66(2):191–201

    Article  PubMed  Google Scholar 

  • Mishto M, Bellavista E et al (2006) Immunoproteasome and LMP2 polymorphism in aged and Alzheimer’s disease brains. Neurobiol Aging 27(1):54–66

    Article  CAS  PubMed  Google Scholar 

  • Myeku N, Clelland CL et al (2016) Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling. Nat Med 22(1):46–53

    Article  CAS  PubMed  Google Scholar 

  • Nair SK, Snyder D et al (1997) Regression of tumors in mice vaccinated with professional antigen-presenting cells pulsed with tumor extracts. Int J Cancer 70(6):706–715

    Article  CAS  PubMed  Google Scholar 

  • Nijholt DA, de Graaf TR et al (2011) Endoplasmic reticulum stress activates autophagy but not the proteasome in neuronal cells: implications for Alzheimer’s disease. Cell Death Differ 18(6):1071–1081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Opitz E, Koch A et al (2011) Impairment of immunoproteasome function by beta5i/LMP7 subunit deficiency results in severe enterovirus myocarditis. PLoS Pathog 7(9):e1002233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Orlowski RZ, Kuhn DJ (2008) Proteasome inhibitors in cancer therapy: lessons from the first decade. Clin Cancer Res 14(6):1649–1657

    Article  CAS  PubMed  Google Scholar 

  • Orlowski RZ, Eswara JR et al (1998) Tumor growth inhibition induced in a murine model of human Burkitt's lymphoma by a proteasome inhibitor. Cancer Res 58(19):4342–4348

    CAS  PubMed  Google Scholar 

  • Orlowski RZ, Kuhn DJ et al (2005) Identification of novel inhibitors that specifically target the immunoproteasome, and selectively induce apoptosis in multiple myeloma and other immunoproteasome-expressing model systems. Blood 106(11):76a

    Google Scholar 

  • Orre M, Kamphuis W et al (2013) Reactive glia show increased immunoproteasome activity in Alzheimer’s disease. Brain 136(Pt 5):1415–1431

    Article  PubMed  Google Scholar 

  • Peng X, Thierry-Mieg J et al (2015) Tissue-specific transcriptome sequencing analysis expands the non-human primate reference transcriptome resource (NHPRTR). Nucleic Acids Res 43(Database issue):D737–D742

    Article  CAS  PubMed  Google Scholar 

  • Perez VI, Buffenstein R et al (2009) Protein stability and resistance to oxidative stress are determinants of longevity in the longest-living rodent, the naked mole-rat. Proc Natl Acad Sci U S A 106(9):3059–3064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Petropoulos I, Conconi M et al (2000) Increase of oxidatively modified protein is associated with a decrease of proteasome activity and content in aging epidermal cells. J Gerontol A Biol Sci Med Sci 55(5):B220–B227

    Article  CAS  PubMed  Google Scholar 

  • Pickering AM, Davies KJ (2012) Differential roles of proteasome and immunoproteasome regulators Pa28alphabeta, Pa28gamma and Pa200 in the degradation of oxidized proteins. Arch Biochem Biophys 523(2):181–190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pickering AM, Koop AL et al (2010) The immunoproteasome, the 20S proteasome and the PA28alphabeta proteasome regulator are oxidative-stress-adaptive proteolytic complexes. Biochem J 432(3):585–594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pickering AM, Lehr M et al (2015) Lifespan of mice and primates correlates with immunoproteasome expression. J Clin Invest 125(5):2059–2068

    Article  PubMed  PubMed Central  Google Scholar 

  • Ponnappan U, Zhong M et al (1999) Decreased proteasome-mediated degradation in T cells from the elderly: a role in immune senescence. Cell Immunol 192(2):167–174

    Article  CAS  PubMed  Google Scholar 

  • Poppek D, Keck S et al (2006) Phosphorylation inhibits turnover of the tau protein by the proteasome: influence of RCAN1 and oxidative stress. Biochem J 400(3):511–520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Puttaparthi K, Elliott JL (2005) Non-neuronal induction of immunoproteasome subunits in an ALS model: possible mediation by cytokines. Exp Neurol 196(2):441–451

    Article  CAS  PubMed  Google Scholar 

  • Rodriguez KA, Edrey YH et al (2012) Altered composition of liver proteasome assemblies contributes to enhanced proteasome activity in the exceptionally long-lived naked mole-rat. PLoS One 7(5):e35890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shang F, Gong X et al (1997) Age-related decline in ubiquitin conjugation in response to oxidative stress in the lens. Exp Eye Res 64(1):21–30

    Article  CAS  PubMed  Google Scholar 

  • Shibatani T, Nazir M et al (1996) Alteration of rat liver 20S proteasome activities by age and food restriction. J Gerontol A Biol Sci Med Sci 51(5):B316–B322

    Article  CAS  PubMed  Google Scholar 

  • Shimizu Y, Geraghty DE et al (1988) Transfer and expression of three cloned human non-HLA-A,B,C class I major histocompatibility complex genes in mutant lymphoblastoid cells. Proc Natl Acad Sci U S A 85(1):227–231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shringarpure R, Grune T et al (2001) Protein oxidation and 20S proteasome-dependent proteolysis in mammalian cells. Cell Mol Life Sci 58(10):1442–1450

    Article  CAS  PubMed  Google Scholar 

  • Stauber AJ, Brown-Borg H et al (2005) Constitutive expression of peroxisome proliferator-activated receptor alpha-regulated genes in dwarf mice. Mol Pharmacol 67(3):681–694

    Article  CAS  PubMed  Google Scholar 

  • Stratford FL, Chondrogianni N et al (2006) Proteasome response to interferon-gamma is altered in senescent human fibroblasts. FEBS Lett 580(16):3989–3994

    Article  CAS  PubMed  Google Scholar 

  • Strong R, Miller RA et al (2008) Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice. Aging Cell 7(5):641–650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tanahashi N, Tsurumi C et al (1993) Molecular structure of 20S and 26S proteasomes. Enzyme Protein 47(4–6):241–251

    Article  CAS  PubMed  Google Scholar 

  • Tanaka K, Kasahara M (1998) The MHC class I ligand-generating system: roles of immunoproteasomes and the interferon-gamma-inducible proteasome activator PA28. Immunol Rev 163:161–176

    Article  CAS  PubMed  Google Scholar 

  • Van Kaer L, Ashton-Rickardt PG et al (1994) Altered peptidase and viral-specific T cell response in LMP2 mutant mice. Immunity 1(7):533–541

    Article  PubMed  Google Scholar 

  • Vernace VA, Arnaud L et al (2007) Aging perturbs 26S proteasome assembly in Drosophila Melanogaster. FASEB J 21(11):2672–2682

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vilchez D, Boyer L et al (2012) Increased proteasome activity in human embryonic stem cells is regulated by PSMD11. Nature 489(7415):304–308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Viteri G, Carrard G et al (2004) Age-dependent protein modifications and declining proteasome activity in the human lens. Arch Biochem Biophys 427(2):197–203

    Article  CAS  PubMed  Google Scholar 

  • Zia A, Schildberg FW et al (2001) MHC class I negative phenotype of disseminated tumor cells in bone marrow is associated with poor survival in R0M0 breast cancer patients. Int J Cancer 93(4):566–570

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported by the National Institute of Aging, a division of the NIH (grants P30-AG024824, U19-AG023122, R01-AG019899, T32-AG000114, F32-AG049555), as well as by the Glenn Foundation for Medical Research.

Author information

Authors and Affiliations

  1. Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI, USA

    Richard A. Miller

  2. Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Andrew M. Pickering

Authors
  1. Andrew M. Pickering
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard A. Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrew M. Pickering .

Editor information

Editors and Affiliations

  1. Division of Geriatrics Research Center on Aging, University of Sherbrooke Dept. of Medicine, Sherbrooke, Québec, Canada

    Tamas Fulop

  2. Dept of Experimental Pathology, University of Bologna, Bologna, Italy

    Claudio Franceschi

  3. Institute for Health and Life Sciences, Tokyo, Japan

    Katsuiku Hirokawa

  4. Center for Medical Research, University of Tübingen, Tübingen, Germany

    Graham Pawelec

Section Editor information

  1. Research Center on Aging, Department of Medicine, Immunology Graduate Programme, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Quebec, Canada

    Tamas Fulop

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Pickering, A.M., Miller, R.A. (2018). Immunoproteasome System in Aging, Lifespan, and Age-Associated Disease. In: Fulop, T., Franceschi, C., Hirokawa, K., Pawelec, G. (eds) Handbook of Immunosenescence. Springer, Cham. https://doi.org/10.1007/978-3-319-64597-1_111-1

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-64597-1_111-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-64597-1

  • Online ISBN: 978-3-319-64597-1

  • eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences

Publish with us

Policies and ethics

Search

Navigation