1. Function

2. Clinical significance

3. Interactions

4. References

5. Further reading

Function

The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes a non-ATPase subunit of the 19S regulator base.^[2]

Clinical significance

The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.

The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) ^[3] and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis.^[4] Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases,^[5][6] cardiovascular diseases,^[7][8][9] inflammatory responses and autoimmune diseases,^[10] and systemic DNA damage responses leading to malignancies.^[11]

Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease,^[12] Parkinson's disease^[13] and Pick's disease,^[14] Amyotrophic lateral sclerosis (ALS),^[14] Huntington's disease,^[13] Creutzfeldt–Jakob disease,^[15] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies^[16] and several rare forms of neurodegenerative diseases associated with dementia.^[17] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,^[18] ventricular hypertrophy^[19] and Heart failure.^[20] Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies.^[21] Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO).^[10] Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors.^[22] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.^[23]

Interactions

PSMD5 has been shown to interact with PSMC2.^[24][25]

References

Further reading

• {{cite journal | vauthors = Coux O, Tanaka K, Goldberg AL | title = Structure and functions of the 20S and 26S proteasomes. | journal = Annu. Rev. Biochem. | volume = 65 | issue = | pages = 801–47 | year = 1996 | pmid = 8811196 | doi = 10.1146/annurev.bi.65.070196.004101 }}
• {{cite journal | vauthors = Goff SP | title = Death by deamination: a novel host restriction system for HIV-1. | journal = Cell | volume = 114 | issue = 3 | pages = 281–3 | year = 2003 | pmid = 12914693 | doi = 10.1016/S0092-8674(03)00602-0 }}
• {{cite journal | vauthors = Kanayama HO, Tamura T, Ugai S, Kagawa S, Tanahashi N, Yoshimura T, Tanaka K, Ichihara A | title = Demonstration that a human 26S proteolytic complex consists of a proteasome and multiple associated protein components and hydrolyzes ATP and ubiquitin-ligated proteins by closely linked mechanisms. | journal = Eur. J. Biochem. | volume = 206 | issue = 2 | pages = 567–78 | year = 1992 | pmid = 1317798 | doi = 10.1111/j.1432-1033.1992.tb16961.x }}
• {{cite journal | vauthors = Nomura N, Nagase T, Miyajima N, Sazuka T, Tanaka A, Sato S, Seki N, Kawarabayasi Y, Ishikawa K, Tabata S | title = Prediction of the coding sequences of unidentified human genes. II. The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis of cDNA clones from human cell line KG-1. | journal = DNA Res. | volume = 1 | issue = 5 | pages = 223–9 | year = 1995 | pmid = 7584044 | doi = 10.1093/dnares/1.5.223 }}
• {{cite journal | vauthors = Deveraux Q, Ustrell V, Pickart C, Rechsteiner M | title = A 26 S protease subunit that binds ubiquitin conjugates. | journal = J. Biol. Chem. | volume = 269 | issue = 10 | pages = 7059–61 | year = 1994 | pmid = 8125911 | doi = }}
• {{cite journal | vauthors = Seeger M, Ferrell K, Frank R, Dubiel W | title = HIV-1 tat inhibits the 20 S proteasome and its 11 S regulator-mediated activation. | journal = J. Biol. Chem. | volume = 272 | issue = 13 | pages = 8145–8 | year = 1997 | pmid = 9079628 | doi = 10.1074/jbc.272.13.8145 }}
• {{cite journal | vauthors = Madani N, Kabat D | title = An endogenous inhibitor of human immunodeficiency virus in human lymphocytes is overcome by the viral Vif protein. | journal = J. Virol. | volume = 72 | issue = 12 | pages = 10251–5 | year = 1998 | pmid = 9811770 | pmc = 110608 | doi = }}
• {{cite journal | vauthors = Simon JH, Gaddis NC, Fouchier RA, Malim MH | title = Evidence for a newly discovered cellular anti-HIV-1 phenotype. | journal = Nat. Med. | volume = 4 | issue = 12 | pages = 1397–400 | year = 1998 | pmid = 9846577 | doi = 10.1038/3987 }}
• {{cite journal | vauthors = Gorbea C, Taillandier D, Rechsteiner M | title = Mapping subunit contacts in the regulatory complex of the 26 S proteasome. S2 and S5b form a tetramer with ATPase subunits S4 and S7. | journal = J. Biol. Chem. | volume = 275 | issue = 2 | pages = 875–82 | year = 2000 | pmid = 10625621 | doi = 10.1074/jbc.275.2.875 }}
• {{cite journal | vauthors = Mulder LC, Muesing MA | title = Degradation of HIV-1 integrase by the N-end rule pathway. | journal = J. Biol. Chem. | volume = 275 | issue = 38 | pages = 29749–53 | year = 2000 | pmid = 10893419 | doi = 10.1074/jbc.M004670200 }}
• {{cite journal | vauthors = Sheehy AM, Gaddis NC, Choi JD, Malim MH | title = Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein | journal = Nature | volume = 418 | issue = 6898 | pages = 646–50 | year = 2002 | pmid = 12167863 | doi = 10.1038/nature00939 | bibcode = 2002Natur.418..646S }}
• {{cite journal | vauthors = Huang X, Seifert U, Salzmann U, Henklein P, Preissner R, Henke W, Sijts AJ, Kloetzel PM, Dubiel W | title = The RTP site shared by the HIV-1 Tat protein and the 11S regulator subunit alpha is crucial for their effects on proteasome function including antigen processing. | journal = J. Mol. Biol. | volume = 323 | issue = 4 | pages = 771–82 | year = 2002 | pmid = 12419264 | doi = 10.1016/S0022-2836(02)00998-1 }}
• {{cite journal | vauthors = Gevaert K, Goethals M, Martens L, Van Damme J, Staes A, Thomas GR, Vandekerckhove J | title = Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides. | journal = Nat. Biotechnol. | volume = 21 | issue = 5 | pages = 566–9 | year = 2004 | pmid = 12665801 | doi = 10.1038/nbt810 }}
• {{cite journal | vauthors = Gaddis NC, Chertova E, Sheehy AM, Henderson LE, Malim MH | title = Comprehensive investigation of the molecular defect in vif-deficient human immunodeficiency virus type 1 virions. | journal = J. Virol. | volume = 77 | issue = 10 | pages = 5810–20 | year = 2003 | pmid = 12719574 | pmc = 154025 | doi = 10.1128/JVI.77.10.5810-5820.2003 }}
• {{cite journal | vauthors = Lecossier D, Bouchonnet F, Clavel F, Hance AJ | title = Hypermutation of HIV-1 DNA in the absence of the Vif protein. | journal = Science | volume = 300 | issue = 5622 | pages = 1112 | year = 2003 | pmid = 12750511 | doi = 10.1126/science.1083338 }}
• {{cite journal | vauthors = Zhang H, Yang B, Pomerantz RJ, Zhang C, Arunachalam SC, Gao L | title = The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA | journal = Nature | volume = 424 | issue = 6944 | pages = 94–8 | year = 2003 | pmid = 12808465 | pmc = 1350966 | doi = 10.1038/nature01707 | bibcode = 2003Natur.424...94Z }}
• {{cite journal | vauthors = Mangeat B, Turelli P, Caron G, Friedli M, Perrin L, Trono D | title = Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts | journal = Nature | volume = 424 | issue = 6944 | pages = 99–103 | year = 2003 | pmid = 12808466 | doi = 10.1038/nature01709 | bibcode = 2003Natur.424...99M }}

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