PSMD11

Proteasome 26S subunit, non-ATPase 11
Identifiers
Symbols	PSMD11 ; Rpn6; S9; p44.5
External IDs	OMIM: 604449 MGI: 1916327 HomoloGene: 2108 GeneCards: PSMD11 Gene
Gene ontology Molecular function • protein binding Cellular component • proteasome complex • nucleus • nucleoplasm • cytosol • proteasome regulatory particle • membrane • proteasome accessory complex • extracellular exosome Biological process • G1/S transition of mitotic cell cycle • protein polyubiquitination • mitotic cell cycle • stimulatory C-type lectin receptor signaling pathway • antigen processing and presentation of peptide antigen via MHC class I • antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent • ubiquitin-dependent protein catabolic process • regulation of cellular amino acid metabolic process • apoptotic process • DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest • gene expression • programmed cell death • viral process • anaphase-promoting complex-dependent proteasomal ubiquitin-dependent protein catabolic process • cellular nitrogen compound metabolic process • antigen processing and presentation of exogenous peptide antigen via MHC class I • regulation of apoptotic process • negative regulation of apoptotic process • proteasome assembly • small molecule metabolic process • innate immune response • stem cell differentiation • negative regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle • positive regulation of ubiquitin-protein ligase activity involved in regulation of mitotic cell cycle transition • regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle • negative regulation of canonical Wnt signaling pathway • positive regulation of canonical Wnt signaling pathway Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5717	69077
Ensembl	ENSG00000108671	ENSMUSG00000017428
UniProt	O00231	Q8BG32
RefSeq (mRNA)	NM_001270482	NM_178616
RefSeq (protein)	NP_001257411	NP_848731
Location (UCSC)	Chr 17: 32.44 – 32.48 Mb	Chr 11: 80.43 – 80.47 Mb
PubMed search

26S proteasome non-ATPase regulatory subunit 11 is an enzyme that in humans is encoded by the PSMD11 gene.^[1][2][3]

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.^[3]

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) ^[4] 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.^[5] 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,^[6][7] cardiovascular diseases,^[8][9][10] inflammatory responses and autoimmune diseases,^[11] and systemic DNA damage responses leading to malignancies.^[12]

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,^[13] Parkinson's disease^[14] and Pick's disease,^[15] Amyotrophic lateral sclerosis (ALS),^[15] Huntington's disease,^[14] Creutzfeldt-Jacob disease,^[16] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies^[17] and several rare forms of neurodegenerative diseases associated with dementia.^[18] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,^[19] ventricular hypertrophy^[20] and Heart failure.^[21] 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.^[22] 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 selectine) and prostaglandins and nitric oxide (NO).^[11] 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.^[23] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.^[24]

Gene expression levels of the proteasomal subunits (PSMA1, PSMA5, PSMB4, PSMB5 and PSMD1) were investigated in 80 patients with neuroendocrine pulmonary tumors and compared to controls. The study reviled that PSMB4 mRNA was significantly associated with proliferative activity of neuroendocrine pulmonary tumors.^[25] However, a role of PSMA5 was also indicated in neuroendocrine pulmonary tumors. The PSMA5 protein has further been associated with the biosynthesis of conjugated linoleum acid (CLA) in mammary tissue.^[26]

References

1. Saito A, Watanabe TK, Shimada Y, Fujiwara T, Slaughter CA, DeMartino GN, Tanahashi N, Tanaka K (Dec 1997). "cDNA cloning and functional analysis of p44.5 and p55, two regulatory subunits of the 26S proteasome". Gene 203 (2): 241–50. doi:10.1016/S0378-1119(97)00524-6. PMID 9426256.
2. Hoffman L, Rechsteiner M (Mar 1997). "Molecular cloning and expression of subunit 9 of the 26S proteasome". FEBS Letters 404 (2–3): 179–84. doi:10.1016/S0014-5793(97)00126-9. PMID 9119060.
3. "Entrez Gene: PSMD11 proteasome (prosome, macropain) 26S subunit, non-ATPase, 11".
4. Kleiger G, Mayor T (Jun 2014). "Perilous journey: a tour of the ubiquitin-proteasome system". Trends in Cell Biology 24 (6): 352–9. doi:10.1016/j.tcb.2013.12.003. PMC 4037451. PMID 24457024.
5. Goldberg AL, Stein R, Adams J (Aug 1995). "New insights into proteasome function: from archaebacteria to drug development". Chemistry & Biology 2 (8): 503–8. doi:10.1016/1074-5521(95)90182-5. PMID 9383453.
6. Sulistio YA, Heese K (Jan 2015). "The Ubiquitin-Proteasome System and Molecular Chaperone Deregulation in Alzheimer's Disease". Molecular Neurobiology. doi:10.1007/s12035-014-9063-4. PMID 25561438.
7. Ortega Z, Lucas JJ (2014). "Ubiquitin-proteasome system involvement in Huntington's disease". Frontiers in Molecular Neuroscience 7: 77. doi:10.3389/fnmol.2014.00077. PMC 4179678. PMID 25324717.
8. Sandri M, Robbins J (Jun 2014). "Proteotoxicity: an underappreciated pathology in cardiac disease". Journal of Molecular and Cellular Cardiology 71: 3–10. doi:10.1016/j.yjmcc.2013.12.015. PMC 4011959. PMID 24380730.
9. Drews O, Taegtmeyer H (Dec 2014). "Targeting the ubiquitin-proteasome system in heart disease: the basis for new therapeutic strategies". Antioxidants & Redox Signaling 21 (17): 2322–43. doi:10.1089/ars.2013.5823. PMC 4241867. PMID 25133688.
10. Wang ZV, Hill JA (Feb 2015). "Protein quality control and metabolism: bidirectional control in the heart". Cell Metabolism 21 (2): 215–26. doi:10.1016/j.cmet.2015.01.016. PMC 4317573. PMID 25651176.
11. Karin M, Delhase M (Feb 2000). "The I kappa B kinase (IKK) and NF-kappa B: key elements of proinflammatory signalling". Seminars in Immunology 12 (1): 85–98. doi:10.1006/smim.2000.0210. PMID 10723801.
12. Ermolaeva MA, Dakhovnik A, Schumacher B (Sep 2015). "Quality control mechanisms in cellular and systemic DNA damage responses". Ageing Research Reviews 23 (Pt A): 3–11. doi:10.1016/j.arr.2014.12.009. PMID 25560147.
13. Checler F, da Costa CA, Ancolio K, Chevallier N, Lopez-Perez E, Marambaud P (Jul 2000). "Role of the proteasome in Alzheimer's disease". Biochimica et Biophysica Acta 1502 (1): 133–8. doi:10.1016/s0925-4439(00)00039-9. PMID 10899438.
14. Chung KK, Dawson VL, Dawson TM (Nov 2001). "The role of the ubiquitin-proteasomal pathway in Parkinson's disease and other neurodegenerative disorders". Trends in Neurosciences 24 (11 Suppl): S7–14. doi:10.1016/s0166-2236(00)01998-6. PMID 11881748.
15. Ikeda K, Akiyama H, Arai T, Ueno H, Tsuchiya K, Kosaka K (Jul 2002). "Morphometrical reappraisal of motor neuron system of Pick's disease and amyotrophic lateral sclerosis with dementia". Acta Neuropathologica 104 (1): 21–8. doi:10.1007/s00401-001-0513-5. PMID 12070660.
16. Manaka H, Kato T, Kurita K, Katagiri T, Shikama Y, Kujirai K, Kawanami T, Suzuki Y, Nihei K, Sasaki H (May 1992). "Marked increase in cerebrospinal fluid ubiquitin in Creutzfeldt-Jakob disease". Neuroscience Letters 139 (1): 47–9. doi:10.1016/0304-3940(92)90854-z. PMID 1328965.
17. Mathews KD, Moore SA (Jan 2003). "Limb-girdle muscular dystrophy". Current Neurology and Neuroscience Reports 3 (1): 78–85. doi:10.1007/s11910-003-0042-9. PMID 12507416.
18. Mayer RJ (Mar 2003). "From neurodegeneration to neurohomeostasis: the role of ubiquitin". Drug News & Perspectives 16 (2): 103–8. doi:10.1358/dnp.2003.16.2.829327. PMID 12792671.
19. Calise J, Powell SR (Feb 2013). "The ubiquitin proteasome system and myocardial ischemia". American Journal of Physiology. Heart and Circulatory Physiology 304 (3): H337–49. doi:10.1152/ajpheart.00604.2012. PMC 3774499. PMID 23220331.
20. Predmore JM, Wang P, Davis F, Bartolone S, Westfall MV, Dyke DB, Pagani F, Powell SR, Day SM (Mar 2010). "Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies". Circulation 121 (8): 997–1004. doi:10.1161/CIRCULATIONAHA.109.904557. PMC 2857348. PMID 20159828.
21. Powell SR (Jul 2006). "The ubiquitin-proteasome system in cardiac physiology and pathology". American Journal of Physiology. Heart and Circulatory Physiology 291 (1): H1–H19. doi:10.1152/ajpheart.00062.2006. PMID 16501026.
22. Adams J (Apr 2003). "Potential for proteasome inhibition in the treatment of cancer". Drug Discovery Today 8 (7): 307–15. doi:10.1016/s1359-6446(03)02647-3. PMID 12654543.
23. Ben-Neriah Y (Jan 2002). "Regulatory functions of ubiquitination in the immune system". Nature Immunology 3 (1): 20–6. doi:10.1038/ni0102-20. PMID 11753406.
24. Egerer K, Kuckelkorn U, Rudolph PE, Rückert JC, Dörner T, Burmester GR, Kloetzel PM, Feist E (Oct 2002). "Circulating proteasomes are markers of cell damage and immunologic activity in autoimmune diseases". The Journal of Rheumatology 29 (10): 2045–52. PMID 12375310.
25. Mairinger FD, Walter RF, Theegarten D, Hager T, Vollbrecht C, Christoph DC, Worm K, Ting S, Werner R, Stamatis G, Mairinger T, Baba H, Zarogoulidis K, Huang H, Li Q, Tsakiridis K, Zarogoulidis P, Schmid KW, Wohlschlaeger J (2014). "Gene Expression Analysis of the 26S Proteasome Subunit PSMB4 Reveals Significant Upregulation, Different Expression and Association with Proliferation in Human Pulmonary Neuroendocrine Tumours". Journal of Cancer 5 (8): 646–54. doi:10.7150/jca.9955. PMC 4142326. PMID 25157275.
26. Jin YC, Li ZH, Hong ZS, Xu CX, Han JA, Choi SH, Yin JL, Zhang QK, Lee KB, Kang SK, Song MK, Kim YJ, Kang HS, Choi YJ, Lee HG (Aug 2012). "Conjugated linoleic acid synthesis-related protein proteasome subunit α 5 (PSMA5) is increased by vaccenic acid treatment in goat mammary tissue". Journal of Dairy Science 95 (8): 4286–97. doi:10.3168/jds.2011-4281. PMID 22818443.

Further reading

• Coux O, Tanaka K, Goldberg AL (1996). "Structure and functions of the 20S and 26S proteasomes". Annual Review of Biochemistry 65: 801–47. doi:10.1146/annurev.bi.65.070196.004101. PMID 8811196.
• Goff SP (Aug 2003). "Death by deamination: a novel host restriction system for HIV-1". Cell 114 (3): 281–3. doi:10.1016/S0092-8674(03)00602-0. PMID 12914693.
• Kanayama HO, Tamura T, Ugai S, Kagawa S, Tanahashi N, Yoshimura T, Tanaka K, Ichihara A (Jun 1992). "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". European Journal of Biochemistry / FEBS 206 (2): 567–78. doi:10.1111/j.1432-1033.1992.tb16961.x. PMID 1317798.
• Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Seeger M, Ferrell K, Frank R, Dubiel W (Mar 1997). "HIV-1 tat inhibits the 20 S proteasome and its 11 S regulator-mediated activation". The Journal of Biological Chemistry 272 (13): 8145–8. doi:10.1074/jbc.272.13.8145. PMID 9079628.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Madani N, Kabat D (Dec 1998). "An endogenous inhibitor of human immunodeficiency virus in human lymphocytes is overcome by the viral Vif protein". Journal of Virology 72 (12): 10251–5. PMC 110608. PMID 9811770.
• Simon JH, Gaddis NC, Fouchier RA, Malim MH (Dec 1998). "Evidence for a newly discovered cellular anti-HIV-1 phenotype". Nature Medicine 4 (12): 1397–400. doi:10.1038/3987. PMID 9846577.
• Mulder LC, Muesing MA (Sep 2000). "Degradation of HIV-1 integrase by the N-end rule pathway". The Journal of Biological Chemistry 275 (38): 29749–53. doi:10.1074/jbc.M004670200. PMID 10893419.
• Sheehy AM, Gaddis NC, Choi JD, Malim MH (Aug 2002). "Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein". Nature 418 (6898): 646–50. Bibcode:2002Natur.418..646S. doi:10.1038/nature00939. PMID 12167863.
• Fong A, Zhang M, Neely J, Sun SC (Oct 2002). "S9, a 19 S proteasome subunit interacting with ubiquitinated NF-kappaB2/p100". The Journal of Biological Chemistry 277 (43): 40697–702. doi:10.1074/jbc.M205330200. PMID 12185077.
• Huang X, Seifert U, Salzmann U, Henklein P, Preissner R, Henke W, Sijts AJ, Kloetzel PM, Dubiel W (Nov 2002). "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 of Molecular Biology 323 (4): 771–82. doi:10.1016/S0022-2836(02)00998-1. PMID 12419264.
• Gevaert K, Goethals M, Martens L, Van Damme J, Staes A, Thomas GR, Vandekerckhove J (May 2003). "Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides". Nature Biotechnology 21 (5): 566–9. doi:10.1038/nbt810. PMID 12665801.
• Gaddis NC, Chertova E, Sheehy AM, Henderson LE, Malim MH (May 2003). "Comprehensive investigation of the molecular defect in vif-deficient human immunodeficiency virus type 1 virions". Journal of Virology 77 (10): 5810–20. doi:10.1128/JVI.77.10.5810-5820.2003. PMC 154025. PMID 12719574.
• Lecossier D, Bouchonnet F, Clavel F, Hance AJ (May 2003). "Hypermutation of HIV-1 DNA in the absence of the Vif protein". Science 300 (5622): 1112. doi:10.1126/science.1083338. PMID 12750511.
• Zhang H, Yang B, Pomerantz RJ, Zhang C, Arunachalam SC, Gao L (Jul 2003). "The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA". Nature 424 (6944): 94–8. Bibcode:2003Natur.424...94Z. doi:10.1038/nature01707. PMC 1350966. PMID 12808465.