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. Two transcripts encoding different isoforms have been described.^[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–Jakob 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-selectin) 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]

Interactions

PSMD13 has been shown to interact with PSMC4^[27] and PSMD6.^[27]

References

Further reading

• {{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 | date = Aug 2003 | pmid = 12914693 | doi = 10.1016/S0092-8674(03)00602-0 }}
• {{cite journal | vauthors = Maruyama K, Sugano S | title = Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides | journal = Gene | volume = 138 | issue = 1–2 | pages = 171–4 | date = Jan 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }}
• {{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 = The Journal of Biological Chemistry | volume = 272 | issue = 13 | pages = 8145–8 | date = Mar 1997 | pmid = 9079628 | doi = 10.1074/jbc.272.13.8145 }}
• {{cite journal | vauthors = Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S | title = Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library | journal = Gene | volume = 200 | issue = 1–2 | pages = 149–56 | date = Oct 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }}
• {{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 = Journal of Virology | volume = 72 | issue = 12 | pages = 10251–5 | date = Dec 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 = Nature Medicine | volume = 4 | issue = 12 | pages = 1397–400 | date = Dec 1998 | pmid = 9846577 | doi = 10.1038/3987 }}
• {{cite journal | vauthors = Hoffman L, Gorbea C, Rechsteiner M | title = Identification, molecular cloning, and characterization of subunit 11 of the human 26S proteasome | journal = FEBS Letters | volume = 449 | issue = 1 | pages = 88–92 | date = Apr 1999 | pmid = 10225435 | doi = 10.1016/S0014-5793(99)00403-2 }}
• {{cite journal | vauthors = Roperch JP, Lethrone F, Prieur S, Piouffre L, Israeli D, Tuynder M, Nemani M, Pasturaud P, Gendron MC, Dausset J, Oren M, Amson RB, Telerman A | title = SIAH-1 promotes apoptosis and tumor suppression through a network involving the regulation of protein folding, unfolding, and trafficking: identification of common effectors with p53 and p21(Waf1) | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 14 | pages = 8070–3 | date = Jul 1999 | pmid = 10393949 | pmc = 22189 | doi = 10.1073/pnas.96.14.8070 | bibcode = 1999PNAS...96.8070R }}
• {{cite journal | vauthors = Mulder LC, Muesing MA | title = Degradation of HIV-1 integrase by the N-end rule pathway | journal = The Journal of Biological Chemistry | volume = 275 | issue = 38 | pages = 29749–53 | date = Sep 2000 | pmid = 10893419 | doi = 10.1074/jbc.M004670200 }}
• {{cite journal | vauthors = Zhang QH, Ye M, Wu XY, Ren SX, Zhao M, Zhao CJ, Fu G, Shen Y, Fan HY, Lu G, Zhong M, Xu XR, Han ZG, Zhang JW, Tao J, Huang QH, Zhou J, Hu GX, Gu J, Chen SJ, Chen Z | title = Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells | journal = Genome Research | volume = 10 | issue = 10 | pages = 1546–60 | date = Oct 2000 | pmid = 11042152 | pmc = 310934 | doi = 10.1101/gr.140200 }}
• {{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 | date = Aug 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 = Journal of Molecular Biology | volume = 323 | issue = 4 | pages = 771–82 | date = Nov 2002 | pmid = 12419264 | doi = 10.1016/S0022-2836(02)00998-1 }}
• {{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 = Journal of Virology | volume = 77 | issue = 10 | pages = 5810–20 | date = May 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 | date = May 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 | date = Jul 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 | date = Jul 2003 | pmid = 12808466 | doi = 10.1038/nature01709 | bibcode = 2003Natur.424...99M }}

• Sharath Kuniyil
• Sharat Kovakab
• Sharavana Kshetra
• Sharavathi Bridge
• Sharavathi express
• Sharavathi Express
• Sharavathi River
• Sharavathi Wildlife Sanctuary
• Sharavati Bridge
• Sharavati raga
• Sharavati Wildlife Sanctuary
• Sharav bold
• Sharav Nasanjargal
• Sharavogue
• Sharawadgi
• Sharawaggi
• Sharawand
• Sharaya
• Sharaya Howell
• Sharaya J
• Sharayet
• Sharaz
• Sharazak
• Sharazoor District
• Sharazor