PSMD8

PSMD8
Identifiers
Aliases	PSMD8, HEL-S-91n, HIP6, HYPF, Nin1p, Rpn12, S14, p31, proteasome 26S subunit, non-ATPase 8
External IDs	OMIM: 617844; MGI: 1888669; HomoloGene: 37686; GeneCards: PSMD8; OMA:PSMD8 - orthologs
Gene location (Human) Chr. Chromosome 19 (human)[1] Band 19q13.2 Start 38,374,550 bp[1] End 38,383,824 bp[1]
Gene location (Mouse) Chr. Chromosome 7 (mouse)[2] Band 7|7 B1 Start 28,873,613 bp[2] End 28,880,126 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in gastrocnemius muscle left ventricle stromal cell of endometrium islet of Langerhans skin of abdomen prefrontal cortex triceps brachii muscle subcutaneous adipose tissue smooth muscle tissue thoracic aorta Top expressed in seminiferous tubule triceps brachii muscle lip temporal muscle sternocleidomastoid muscle esophagus abdominal wall medial ganglionic eminence thymus brown adipose tissue More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein binding Cellular component nucleoplasm nucleus proteasome regulatory particle, lid subcomplex proteasome regulatory particle proteasome accessory complex extracellular exosome cytosol proteasome complex Biological process NIK/NF-kappaB signaling proteolysis MAPK cascade proteasome assembly regulation of mRNA stability protein polyubiquitination Fc-epsilon receptor signaling pathway regulation of cellular amino acid metabolic process antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent tumor necrosis factor-mediated signaling pathway regulation of protein stability stimulatory C-type lectin receptor signaling pathway anaphase-promoting complex-dependent catabolic process positive regulation of protein targeting to mitochondrion negative regulation of canonical Wnt signaling pathway T cell receptor signaling pathway positive regulation of canonical Wnt signaling pathway proteasome-mediated ubiquitin-dependent protein catabolic process Wnt signaling pathway, planar cell polarity pathway negative regulation of G2/M transition of mitotic cell cycle protein deubiquitination SCF-dependent proteasomal ubiquitin-dependent protein catabolic process transmembrane transport regulation of transcription from RNA polymerase II promoter in response to hypoxia post-translational protein modification regulation of hematopoietic stem cell differentiation interleukin-1-mediated signaling pathway regulation of mitotic cell cycle phase transition Sources:Amigo / QuickGO
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: 28.87 – 28.88 Mb PubMed search [3] [4]
Wikidata
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26S proteasome non-ATPase regulatory subunit 8 is an enzyme that in humans is encoded by the PSMD8 gene.^[5][6]

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.^[6]

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) ^[7] 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.^[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 to malignancies.^[15]

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,^[16] Parkinson's disease^[17] and Pick's disease,^[18] Amyotrophic lateral sclerosis (ALS),^[18] Huntington's disease,^[17] Creutzfeldt–Jakob disease,^[19] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies^[20] and several rare forms of neurodegenerative diseases associated with dementia.^[21] As part of the ubiquitin–proteasome system (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac ischemic injury,^[22] ventricular hypertrophy^[23] and Heart failure.^[24] 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.^[25] 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).^[14] 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.^[26] Lastly, autoimmune disease patients with SLE, Sjögren syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.^[27]

References

Further reading

External links

• Overview of all the structural information available in the PDB for UniProt: P48556 (26S proteasome non-ATPase regulatory subunit 8) at the PDBe-KB.