PSMD3 explained

26S proteasome non-ATPase regulatory subunit 3 is an enzyme that in humans is encoded by the PSMD3 gene.[1] [2]

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 one of the non-ATPase subunits of the 19S regulator lid.

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, Sjögren syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[23]

Specifically, genetic variants studies at PSMD3 indicated that its involvement in the regulation of insulin signal transduction could be effected by dietary factors. Accordingly, PSMD3 variants appear to be associated with insulin resistance in populations of different ancestries and these relationships can be affected by eating habits.[24] Furthermore, a genome-wide association study (GWAS) has identified that a variant in PSMD3 is associated to neutropenia induced interferon during the therapy of chronic hepatitis C.[25]

During the antigen processing for the major histocompatibility complex (MHC) class-I, the proteasome is the major degradation machinery that degrades the antigen and present the resulting peptides to cytotoxic T lymphocytes.[26] [27] The immunoproteasome has been considered playing a critical role in improving the quality and quantity of generated class-I ligands.

Further reading

Notes and References

  1. Kominami K, Okura N, Kawamura M, DeMartino GN, Slaughter CA, Shimbara N, Chung CH, Fujimuro M, Yokosawa H, Shimizu Y, Tanahashi N, Tanaka K, Toh-e A . Yeast counterparts of subunits S5a and p58 (S3) of the human 26S proteasome are encoded by two multicopy suppressors of nin1-1 . Molecular Biology of the Cell . 8 . 1 . 171–87 . Jan 1997 . 9017604 . 276068 . 10.1091/mbc.8.1.171 .
  2. Web site: Entrez Gene: PSMD3 proteasome (prosome, macropain) 26S subunit, non-ATPase, 3.
  3. Kleiger G, Mayor T . Perilous journey: a tour of the ubiquitin-proteasome system . Trends in Cell Biology . 24 . 6 . 352–9 . Jun 2014 . 24457024 . 4037451 . 10.1016/j.tcb.2013.12.003 .
  4. Goldberg AL, Stein R, Adams J . New insights into proteasome function: from archaebacteria to drug development . Chemistry & Biology . 2 . 8 . 503–8 . Aug 1995 . 9383453 . 10.1016/1074-5521(95)90182-5. free .
  5. Sulistio YA, Heese K . The Ubiquitin-Proteasome System and Molecular Chaperone Deregulation in Alzheimer's Disease . Molecular Neurobiology . Jan 2015 . 25561438 . 10.1007/s12035-014-9063-4 . 53 . 2 . 905–31. 14103185 .
  6. Ortega Z, Lucas JJ . Ubiquitin-proteasome system involvement in Huntington's disease . Frontiers in Molecular Neuroscience . 7 . 77 . 2014 . 25324717 . 4179678 . 10.3389/fnmol.2014.00077 . free .
  7. Sandri M, Robbins J . Proteotoxicity: an underappreciated pathology in cardiac disease . Journal of Molecular and Cellular Cardiology . 71 . 3–10 . Jun 2014 . 24380730 . 4011959 . 10.1016/j.yjmcc.2013.12.015 .
  8. Drews O, Taegtmeyer H . Targeting the ubiquitin-proteasome system in heart disease: the basis for new therapeutic strategies . Antioxidants & Redox Signaling . 21 . 17 . 2322–43 . Dec 2014 . 25133688 . 4241867 . 10.1089/ars.2013.5823 .
  9. Wang ZV, Hill JA . Protein quality control and metabolism: bidirectional control in the heart . Cell Metabolism . 21 . 2 . 215–26 . Feb 2015 . 25651176 . 4317573 . 10.1016/j.cmet.2015.01.016 .
  10. Karin M, Delhase M . The I kappa B kinase (IKK) and NF-kappa B: key elements of proinflammatory signalling . Seminars in Immunology . 12 . 1 . 85–98 . Feb 2000 . 10723801 . 10.1006/smim.2000.0210 .
  11. Ermolaeva MA, Dakhovnik A, Schumacher B . Quality control mechanisms in cellular and systemic DNA damage responses . Ageing Research Reviews . 23 . Pt A . 3–11 . Jan 2015 . 25560147 . 10.1016/j.arr.2014.12.009 . 4886828.
  12. Checler F, da Costa CA, Ancolio K, Chevallier N, Lopez-Perez E, Marambaud P . Role of the proteasome in Alzheimer's disease . Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease . 1502 . 1 . 133–8 . Jul 2000 . 10899438 . 10.1016/s0925-4439(00)00039-9.
  13. Chung KK, Dawson VL, Dawson TM . The role of the ubiquitin-proteasomal pathway in Parkinson's disease and other neurodegenerative disorders . Trends in Neurosciences . 24 . 11 Suppl . S7–14 . Nov 2001 . 11881748 . 10.1016/s0166-2236(00)01998-6. 2211658 .
  14. Ikeda K, Akiyama H, Arai T, Ueno H, Tsuchiya K, Kosaka K . Morphometrical reappraisal of motor neuron system of Pick's disease and amyotrophic lateral sclerosis with dementia . Acta Neuropathologica . 104 . 1 . 21–8 . Jul 2002 . 12070660 . 10.1007/s00401-001-0513-5 . 22396490 .
  15. Manaka H, Kato T, Kurita K, Katagiri T, Shikama Y, Kujirai K, Kawanami T, Suzuki Y, Nihei K, Sasaki H . Marked increase in cerebrospinal fluid ubiquitin in Creutzfeldt–Jakob disease . Neuroscience Letters . 139 . 1 . 47–9 . May 1992 . 1328965 . 10.1016/0304-3940(92)90854-z. 28190967 .
  16. Mathews KD, Moore SA . Limb-girdle muscular dystrophy . Current Neurology and Neuroscience Reports . 3 . 1 . 78–85 . Jan 2003 . 12507416 . 10.1007/s11910-003-0042-9. 5780576 .
  17. Mayer RJ . From neurodegeneration to neurohomeostasis: the role of ubiquitin . Drug News & Perspectives . 16 . 2 . 103–8 . Mar 2003 . 12792671 . 10.1358/dnp.2003.16.2.829327.
  18. Calise J, Powell SR . The ubiquitin proteasome system and myocardial ischemia . American Journal of Physiology. Heart and Circulatory Physiology . 304 . 3 . H337–49 . Feb 2013 . 23220331 . 3774499 . 10.1152/ajpheart.00604.2012 .
  19. Predmore JM, Wang P, Davis F, Bartolone S, Westfall MV, Dyke DB, Pagani F, Powell SR, Day SM . Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies . Circulation . 121 . 8 . 997–1004 . Mar 2010 . 20159828 . 2857348 . 10.1161/CIRCULATIONAHA.109.904557 .
  20. Powell SR . The ubiquitin-proteasome system in cardiac physiology and pathology . American Journal of Physiology. Heart and Circulatory Physiology . 291 . 1 . H1–H19 . Jul 2006 . 16501026 . 10.1152/ajpheart.00062.2006 . 7073263 .
  21. Adams J . Potential for proteasome inhibition in the treatment of cancer . Drug Discovery Today . 8 . 7 . 307–15 . Apr 2003 . 12654543 . 10.1016/s1359-6446(03)02647-3.
  22. Ben-Neriah Y . Regulatory functions of ubiquitination in the immune system . Nature Immunology . 3 . 1 . 20–6 . Jan 2002 . 11753406 . 10.1038/ni0102-20 . 26973319 .
  23. Egerer K, Kuckelkorn U, Rudolph PE, Rückert JC, Dörner T, Burmester GR, Kloetzel PM, Feist E . Circulating proteasomes are markers of cell damage and immunologic activity in autoimmune diseases . The Journal of Rheumatology . 29 . 10 . 2045–52 . Oct 2002 . 12375310 .
  24. Zheng JS, Arnett DK, Parnell LD, Lee YC, Ma Y, Smith CE, Richardson K, Li D, Borecki IB, Ordovas JM, Tucker KL, Lai CQ . Genetic variants at PSMD3 interact with dietary fat and carbohydrate to modulate insulin resistance . The Journal of Nutrition . 143 . 3 . 354–61 . Mar 2013 . 23303871 . 3713024 . 10.3945/jn.112.168401 .
  25. Iio E, Matsuura K, Nishida N, Maekawa S, Enomoto N, Nakagawa M, Sakamoto N, Yatsuhashi H, Kurosaki M, Izumi N, Hiasa Y, Masaki N, Ide T, Hino K, Tamori A, Honda M, Kaneko S, Mochida S, Nomura H, Nishiguchi S, Okuse C, Itoh Y, Yoshiji H, Sakaida I, Yamamoto K, Watanabe H, Hige S, Matsumoto A, Tanaka E, Tokunaga K, Tanaka Y . Genome-wide association study identifies a PSMD3 variant associated with neutropenia in interferon-based therapy for chronic hepatitis C . Human Genetics . 134 . 3 . 279–89 . Mar 2015 . 25515861 . 10.1007/s00439-014-1520-7 . 18891859 .
  26. Basler M, Lauer C, Beck U, Groettrup M . The proteasome inhibitor bortezomib enhances the susceptibility to viral infection . Journal of Immunology . 183 . 10 . 6145–50 . Nov 2009 . 19841190 . 10.4049/jimmunol.0901596 . free .
  27. Rock KL, Gramm C, Rothstein L, Clark K, Stein R, Dick L, Hwang D, Goldberg AL . Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules . Cell . 78 . 5 . 761–71 . Sep 1994 . 8087844 . 10.1016/s0092-8674(94)90462-6. 22262916 .

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