PSMD8

Proteasome 26S subunit, non-ATPase 8
Identifiers
Symbols	PSMD8 ; HEL-S-91n; HIP6; HYPF; Nin1p; Rpn12; S14; p31
External IDs	MGI: 1888669 HomoloGene: 37686 GeneCards: PSMD8 Gene
Gene ontology Molecular function • protein binding Cellular component • proteasome complex • nucleus • nucleoplasm • cytosol • proteasome regulatory particle • 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 • 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 • regulation of protein stability • 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 • small molecule metabolic process • innate immune response • 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 • positive regulation of protein targeting to mitochondrion Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5714	57296
Ensembl	ENSG00000099341	ENSMUSG00000030591
UniProt	P48556	Q9CX56
RefSeq (mRNA)	NM_002812	NM_026545
RefSeq (protein)	NP_002803	NP_080821
Location (UCSC)	Chr 19: 38.37 – 38.38 Mb	Chr 7: 29.17 – 29.18 Mb
PubMed search

26S proteasome non-ATPase regulatory subunit 8 is an enzyme that in humans is encoded by the PSMD8 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 a non-ATPase subunit of the 19S regulator. A pseudogene has been identified on chromosome 1.^[2]

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-Jacob 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 selectine) 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, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.^[23]

References

Further reading