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.[6]
The proteasomes form a pivotal component for theUbiquitin-Proteasome System (UPS)[7] and corresponding cellular Protein Quality Control (PQC). Proteinubiquitination and subsequentproteolysis and degradation by the proteasome are important mechanisms in the regulation of thecell cycle,cell growth and differentiation, gene transcription, signal transduction andapoptosis.[8] 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,[9][10] cardiovascular diseases,[11][12][13] inflammatory responses and autoimmune diseases,[14] and systemic DNA damage responses leading tomalignancies.[15]
Specifically, genetic variants studies at PSMD3 indicated that its involvement in the regulation ofinsulinsignal transduction could be effected by dietary factors. Accordingly, PSMD3 variants appear to be associated withinsulin resistance in populations of different ancestries and these relationships can be affected by eating habits.[28] Furthermore, agenome-wide association study (GWAS) has identified that a variant in PSMD3 is associated toneutropenia inducedinterferon during thetherapy of chronichepatitis C.[29]
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.[30][31] The immunoproteasome has been considered playing a critical role in improving the quality and quantity of generated class-I ligands.
^Sulistio YA, Heese K (Jan 2015). "The Ubiquitin-Proteasome System and Molecular Chaperone Deregulation in Alzheimer's Disease".Molecular Neurobiology.53 (2):905–31.doi:10.1007/s12035-014-9063-4.PMID25561438.S2CID14103185.
^abKarin 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.PMID10723801.
^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 (BBA) - Molecular Basis of Disease.1502 (1):133–8.doi:10.1016/s0925-4439(00)00039-9.PMID10899438.
^abChung 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.PMID11881748.S2CID2211658.
^abIkeda 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.PMID12070660.S2CID22396490.
^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.PMID1328965.S2CID28190967.
^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.PMID16501026.S2CID7073263.
^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.PMID12375310.
^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 (Mar 2015). "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.doi:10.1007/s00439-014-1520-7.PMID25515861.S2CID18891859.
^Rock KL, Gramm C, Rothstein L, Clark K, Stein R, Dick L, Hwang D, Goldberg AL (Sep 1994). "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.doi:10.1016/s0092-8674(94)90462-6.PMID8087844.S2CID22262916.
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.PMID9846577.S2CID25235070.
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.PMID12419264.
Harris RS, Sheehy AM, Craig HM, Malim MH, Neuberger MS (Jul 2003). "DNA deamination: not just a trigger for antibody diversification but also a mechanism for defense against retroviruses".Nature Immunology.4 (7):641–3.doi:10.1038/ni0703-641.PMID12830140.S2CID5549252.
