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PSMD6
Identifiers
Aliases	PSMD6, Rpn7, S10, SGA-113M, p42A, p44S10, proteasome 26S subunit, non-ATPase 6
External IDs	OMIM: 617857; MGI: 1913663; HomoloGene: 7157; GeneCards: PSMD6; OMA:PSMD6 - orthologs
Gene location (Mouse) Chr. Chromosome 14 (mouse) Band 14|14 A1 Start 8,348,779 bp End 8,357,589 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in body of pancreas sperm tibialis anterior muscle gastrocnemius muscle islet of Langerhans deltoid muscle Achilles tendon right adrenal gland triceps brachii muscle left adrenal gland Top expressed in otic placode saccule abdominal wall external carotid artery intercostal muscle internal carotid artery medial ganglionic eminence somite otic vesicle vas deferens More reference expression data BioGPS More reference expression data
Gene ontology Molecular function ATPase activity protein binding enzyme regulator activity Cellular component cytosol proteasome accessory complex proteasome regulatory particle nucleoplasm proteasome complex extracellular region secretory granule lumen ficolin-1-rich granule lumen Biological process proteolysis protein deubiquitination neutrophil degranulation post-translational protein modification regulation of catalytic activity proteasome-mediated ubiquitin-dependent protein catabolic process MAPK cascade protein polyubiquitination stimulatory C-type lectin receptor signaling pathway antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent regulation of cellular amino acid metabolic process negative regulation of G2/M transition of mitotic cell cycle anaphase-promoting complex-dependent catabolic process SCF-dependent proteasomal ubiquitin-dependent protein catabolic process tumor necrosis factor-mediated signaling pathway NIK/NF-kappaB signaling Fc-epsilon receptor signaling pathway regulation of mRNA stability T cell receptor signaling pathway transmembrane transport Wnt signaling pathway, planar cell polarity pathway regulation of transcription from RNA polymerase II promoter in response to hypoxia interleukin-1-mediated signaling pathway negative regulation of canonical Wnt signaling pathway positive regulation of canonical Wnt signaling pathway regulation of mitotic cell cycle phase transition regulation of hematopoietic stem cell differentiation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 9861 66413 Ensembl n/a ENSMUSG00000021737 UniProt Q15008 Q99JI4 RefSeq (mRNA) NM_001271779 NM_001271780 NM_001271781 NM_014814 NM_025550 RefSeq (protein) NP_001258708 NP_001258709 NP_001258710 NP_055629 NP_079826 Location (UCSC) n/a Chr 14: 8.35 – 8.36 Mb PubMed search
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26S proteasome non-ATPase regulatory subunit 6 is an enzyme that in humans is encoded by the PSMD6 gene.

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) 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. 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, cardiovascular diseases, inflammatory responses and autoimmune diseases, and systemic DNA damage responses leading to malignancies.

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, Parkinson's disease and Pick's disease, Amyotrophic lateral sclerosis (ALS), Huntington's disease, Creutzfeldt–Jakob disease, and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies and several rare forms of neurodegenerative diseases associated with dementia. As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury, ventricular hypertrophy and Heart failure. 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. 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). 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. Lastly, autoimmune disease patients with SLE, Sjögren syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.

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. The immunoproteasome has been considered playing a critical role in improving the quality and quantity of generated class-I ligands.

Interactions

PSMD6 has been shown to interact with PSMD13.

References

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Further reading

• Goff SP (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. S2CID 16340355.
• Nagase T, Miyajima N, Tanaka A, Sazuka T, Seki N, Sato S, Tabata S, Ishikawa K, Kawarabayasi Y, Kotani H (1995). "Prediction of the coding sequences of unidentified human genes. III. The coding sequences of 40 new genes (KIAA0081-KIAA0120) deduced by analysis of cDNA clones from human cell line KG-1". DNA Res. 2 (1): 37–43. doi:10.1093/dnares/2.1.37. PMID 7788527.
• Seeger M, Ferrell K, Frank R, Dubiel W (1997). "HIV-1 tat inhibits the 20 S proteasome and its 11 S regulator-mediated activation". J. Biol. Chem. 272 (13): 8145–8. doi:10.1074/jbc.272.13.8145. PMID 9079628.
• Madani N, Kabat D (1998). "An Endogenous Inhibitor of Human Immunodeficiency Virus in Human Lymphocytes Is Overcome by the Viral Vif Protein". J. Virol. 72 (12): 10251–5. doi:10.1128/JVI.72.12.10251-10255.1998. PMC 110608. PMID 9811770.
• Simon JH, Gaddis NC, Fouchier RA, Malim MH (1998). "Evidence for a newly discovered cellular anti-HIV-1 phenotype". Nat. Med. 4 (12): 1397–400. doi:10.1038/3987. PMID 9846577. S2CID 25235070.
• Mulder LC, Muesing MA (2000). "Degradation of HIV-1 integrase by the N-end rule pathway". J. Biol. Chem. 275 (38): 29749–53. doi:10.1074/jbc.M004670200. PMID 10893419.
• Sheehy AM, Gaddis NC, Choi JD, Malim MH (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. S2CID 4403228.
• Huang X, Seifert U, Salzmann U, Henklein P, Preissner R, Henke W, Sijts AJ, Kloetzel PM, Dubiel W (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". J. Mol. Biol. 323 (4): 771–82. doi:10.1016/S0022-2836(02)00998-1. PMID 12419264.
• Gaddis NC, Chertova E, Sheehy AM, Henderson LE, Malim MH (2003). "Comprehensive Investigation of the Molecular Defect in vif-Deficient Human Immunodeficiency Virus Type 1 Virions". J. Virol. 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 (2003). "Hypermutation of HIV-1 DNA in the absence of the Vif protein". Science. 300 (5622): 1112. doi:10.1126/science.1083338. PMID 12750511. S2CID 20591673.
• Zhang H, Yang B, Pomerantz RJ, Zhang C, Arunachalam SC, Gao L (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.
• Mangeat B, Turelli P, Caron G, Friedli M, Perrin L, Trono D (2003). "Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts". Nature. 424 (6944): 99–103. Bibcode:2003Natur.424...99M. doi:10.1038/nature01709. PMID 12808466. S2CID 4347374.
• Harris RS, Bishop KN, Sheehy AM, Craig HM, Petersen-Mahrt SK, Watt IN, Neuberger MS, Malim MH (2003). "DNA deamination mediates innate immunity to retroviral infection". Cell. 113 (6): 803–9. doi:10.1016/S0092-8674(03)00423-9. PMID 12809610. S2CID 544971.
• Harris RS, Sheehy AM, Craig HM, Malim MH, Neuberger MS (2003). "DNA deamination: not just a trigger for antibody diversification but also a mechanism for defense against retroviruses". Nat. Immunol. 4 (7): 641–3. doi:10.1038/ni0703-641. PMID 12830140. S2CID 5549252.
• Gu Y, Sundquist WI (2003). "Good to CU". Nature. 424 (6944): 21–2. Bibcode:2003Natur.424...21G. doi:10.1038/424021a. PMID 12840737. S2CID 4430569.
• Mariani R, Chen D, Schröfelbauer B, Navarro F, König R, Bollman B, Münk C, Nymark-McMahon H, Landau NR (2003). "Species-specific exclusion of APOBEC3G from HIV-1 virions by Vif". Cell. 114 (1): 21–31. doi:10.1016/S0092-8674(03)00515-4. PMID 12859895. S2CID 1789911.
• KewalRamani VN, Coffin JM (2003). "Virology. Weapons of mutational destruction". Science. 301 (5635): 923–5. doi:10.1126/science.1088965. PMID 12920286. S2CID 82480782.

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