# PSMD3

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Enzyme found in humans

PSMD3 Identifiers Aliases PSMD3, P58, RPN3, S3, TSTA2, proteasome 26S subunit, non-ATPase 3 External IDs OMIM: 617676; MGI: 98858; HomoloGene: 2102; GeneCards: PSMD3; OMA:PSMD3 - orthologs Gene location (Human) Chr. Chromosome 17 (human)[1] Band 17q21.1 Start 39,980,807 bp[1] End 39,997,959 bp[1] Gene location (Mouse) Chr. Chromosome 11 (mouse)[2] Band 11 D|11 62.39 cM Start 98,573,380 bp[2] End 98,586,805 bp[2] RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in gastrocnemius muscle muscle of thigh skin of leg mucosa of transverse colon skin of abdomen right hemisphere of cerebellum stromal cell of endometrium ganglionic eminence body of uterus gastric mucosa Top expressed in muscle of thigh lip yolk sac right kidney ventricular zone proximal tubule epiblast superior frontal gyrus primary visual cortex perirhinal cortex More reference expression data BioGPS More reference expression data Gene ontology Molecular function enzyme regulator activity protein binding Cellular component cytosol membrane proteasome accessory complex proteasome regulatory particle proteasome regulatory particle, lid subcomplex proteasome complex extracellular exosome nucleus extracellular region nucleoplasm secretory granule lumen ficolin-1-rich granule lumen Biological process regulation of cellular amino acid metabolic process antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent ubiquitin-dependent protein catabolic process regulation of mRNA stability positive regulation of canonical Wnt signaling pathway protein polyubiquitination stimulatory C-type lectin receptor signaling pathway tumor necrosis factor-mediated signaling pathway MAPK cascade Fc-epsilon receptor signaling pathway NIK/NF-kappaB signaling regulation of protein catabolic process anaphase-promoting complex-dependent catabolic process T cell receptor signaling pathway negative regulation of canonical Wnt signaling pathway Wnt signaling pathway, planar cell polarity pathway proteasome-mediated ubiquitin-dependent protein catabolic process negative regulation of G2/M transition of mitotic cell cycle protein deubiquitination SCF-dependent proteasomal ubiquitin-dependent protein catabolic process neutrophil degranulation transmembrane transport regulation of transcription from RNA polymerase II promoter in response to hypoxia post-translational protein modification regulation of hematopoietic stem cell differentiation regulation of catalytic activity interleukin-1-mediated signaling pathway regulation of mitotic cell cycle phase transition Sources:Amigo / QuickGO Orthologs Species Human Mouse Entrez 5709 22123 Ensembl ENSG00000108344 ENSMUSG00000017221 UniProt O43242 P14685 RefSeq (mRNA) NM_002809 NM_009439 RefSeq (protein) NP_002800 NP_033465 Location (UCSC) Chr 17: 39.98 – 40 Mb Chr 11: 98.57 – 98.59 Mb PubMed search [3] [4] Wikidata View/Edit Human View/Edit Mouse

**26S proteasome non-ATPase regulatory subunit 3** is an [enzyme](/source/Enzyme) that in humans is encoded by the *PSMD3* [gene](/source/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 one of the non-ATPase subunits of the 19S regulator lid.[6]

## Clinical significance

The proteasomes form a pivotal component for the [Ubiquitin-Proteasome System (UPS)](/source/Proteasome)[7] and corresponding cellular Protein Quality Control (PQC). Protein [ubiquitination](/source/Ubiquitination) and subsequent [proteolysis](/source/Proteolysis) and degradation by the proteasome are important mechanisms in the regulation of the [cell cycle](/source/Cell_cycle), [cell growth](/source/Cell_growth) and differentiation, gene transcription, signal transduction and [apoptosis](/source/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](/source/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](/source/Alzheimer's_disease),[16] [Parkinson's disease](/source/Parkinson's_disease)[17] and [Pick's disease](/source/Pick's_disease),[18] [Amyotrophic lateral sclerosis](/source/Amyotrophic_lateral_sclerosis) ([ALS](/source/ALS)),[18] [Huntington's disease](/source/Huntington's_disease),[17] [Creutzfeldt–Jakob disease](/source/Creutzfeldt%E2%80%93Jakob_disease),[19] and motor neuron diseases, polyglutamine (PolyQ) diseases, [Muscular dystrophies](/source/Muscular_dystrophies)[20] and several rare forms of neurodegenerative diseases associated with [dementia](/source/Dementia).[21] As part of the [Ubiquitin-Proteasome System (UPS)](/source/Proteasome), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac [Ischemic](/source/Ischemic) injury,[22] [ventricular hypertrophy](/source/Ventricular_hypertrophy)[23] and [Heart failure](/source/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](/source/Transcription_factors), such as [p53](/source/P53), [c-jun](/source/C-jun), [c-Fos](/source/C-Fos), [NF-κB](/source/NF-%CE%BAB), [c-Myc](/source/C-Myc), HIF-1α, MATα2, [STAT3](/source/STAT3), sterol-regulated element-binding proteins and [androgen receptors](/source/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](/source/Adenomatous_polyposis_coli) ([APC](/source/Adenomatous_polyposis_coli)) in colorectal cancer, [retinoblastoma](/source/Retinoblastoma) (Rb). and [von Hippel–Lindau tumor suppressor](/source/Von_Hippel%E2%80%93Lindau_tumor_suppressor) (VHL), as well as a number of [proto-oncogenes](/source/Proto-oncogenes) ([Raf](/source/Raf_kinase), [Myc](/source/Myc), [Myb](/source/MYB_(gene)), [Rel](/source/NF-%CE%BAB), [Src](/source/Src_(gene)), [Mos](/source/MOS_(gene)), [Abl](/source/Abl_(gene))). 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](/source/Cytokines) such as [TNF-α](/source/TNF-%CE%B1), IL-β, [IL-8](/source/Interleukin_8), [adhesion molecules](/source/Adhesion_molecules) ([ICAM-1](/source/ICAM-1), [VCAM-1](/source/VCAM-1), [P-selectin](/source/P-selectin)) and [prostaglandins](/source/Prostaglandins) and [nitric oxide](/source/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](/source/Cyclin-dependent_kinase) inhibitors.[26] Lastly, [autoimmune disease](/source/Autoimmune_disease) patients with [SLE](/source/Systemic_lupus_erythematosus), [Sjögren syndrome](/source/Sj%C3%B6gren_syndrome) and [rheumatoid arthritis](/source/Rheumatoid_arthritis) (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[27]

Specifically, genetic variants studies at PSMD3 indicated that its involvement in the regulation of [insulin](/source/Insulin) [signal transduction](/source/Signal_transduction) could be effected by dietary factors. Accordingly, PSMD3 variants appear to be associated with [insulin resistance](/source/Insulin_resistance) in populations of different ancestries and these relationships can be affected by eating habits.[28] Furthermore, a [genome-wide association study](/source/Genome-wide_association_study) (GWAS) has identified that a variant in PSMD3 is associated to [neutropenia](/source/Neutropenia) induced [interferon](/source/Interferon) during the [therapy](/source/Therapy) of chronic [hepatitis C](/source/Hepatitis_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.

## References

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1. **[^](#cite_ref-31)** 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](/source/Doi_(identifier)):[10.1016/s0092-8674(94)90462-6](https://doi.org/10.1016%2Fs0092-8674%2894%2990462-6). [PMID](/source/PMID_(identifier)) [8087844](https://pubmed.ncbi.nlm.nih.gov/8087844). [S2CID](/source/S2CID_(identifier)) [22262916](https://api.semanticscholar.org/CorpusID:22262916).

## Further reading

- Coux O, Tanaka K, Goldberg AL (1996). "Structure and functions of the 20S and 26S proteasomes". *Annual Review of Biochemistry*. **65**: 801–47. [doi](/source/Doi_(identifier)):[10.1146/annurev.bi.65.070196.004101](https://doi.org/10.1146%2Fannurev.bi.65.070196.004101). [PMID](/source/PMID_(identifier)) [8811196](https://pubmed.ncbi.nlm.nih.gov/8811196).

- Goff SP (Aug 2003). ["Death by deamination: a novel host restriction system for HIV-1"](https://doi.org/10.1016%2FS0092-8674%2803%2900602-0). *Cell*. **114** (3): 281–3. [doi](/source/Doi_(identifier)):[10.1016/S0092-8674(03)00602-0](https://doi.org/10.1016%2FS0092-8674%2803%2900602-0). [PMID](/source/PMID_(identifier)) [12914693](https://pubmed.ncbi.nlm.nih.gov/12914693). [S2CID](/source/S2CID_(identifier)) [16340355](https://api.semanticscholar.org/CorpusID:16340355).

- Seeger M, Ferrell K, Frank R, Dubiel W (Mar 1997). ["HIV-1 tat inhibits the 20 S proteasome and its 11 S regulator-mediated activation"](https://doi.org/10.1074%2Fjbc.272.13.8145). *The Journal of Biological Chemistry*. **272** (13): 8145–8. [doi](/source/Doi_(identifier)):[10.1074/jbc.272.13.8145](https://doi.org/10.1074%2Fjbc.272.13.8145). [PMID](/source/PMID_(identifier)) [9079628](https://pubmed.ncbi.nlm.nih.gov/9079628).

- Madani N, Kabat D (Dec 1998). ["An endogenous inhibitor of human immunodeficiency virus in human lymphocytes is overcome by the viral Vif protein"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC110608). *Journal of Virology*. **72** (12): 10251–5. [doi](/source/Doi_(identifier)):[10.1128/JVI.72.12.10251-10255.1998](https://doi.org/10.1128%2FJVI.72.12.10251-10255.1998). [PMC](/source/PMC_(identifier)) [110608](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC110608). [PMID](/source/PMID_(identifier)) [9811770](https://pubmed.ncbi.nlm.nih.gov/9811770).

- 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](/source/Doi_(identifier)):[10.1038/3987](https://doi.org/10.1038%2F3987). [PMID](/source/PMID_(identifier)) [9846577](https://pubmed.ncbi.nlm.nih.gov/9846577). [S2CID](/source/S2CID_(identifier)) [25235070](https://api.semanticscholar.org/CorpusID:25235070).

- Mulder LC, Muesing MA (Sep 2000). ["Degradation of HIV-1 integrase by the N-end rule pathway"](https://doi.org/10.1074%2Fjbc.M004670200). *The Journal of Biological Chemistry*. **275** (38): 29749–53. [doi](/source/Doi_(identifier)):[10.1074/jbc.M004670200](https://doi.org/10.1074%2Fjbc.M004670200). [PMID](/source/PMID_(identifier)) [10893419](https://pubmed.ncbi.nlm.nih.gov/10893419).

- Sheehy AM, Gaddis NC, Choi JD, Malim MH (Aug 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](/source/Bibcode_(identifier)):[2002Natur.418..646S](https://ui.adsabs.harvard.edu/abs/2002Natur.418..646S). [doi](/source/Doi_(identifier)):[10.1038/nature00939](https://doi.org/10.1038%2Fnature00939). [PMID](/source/PMID_(identifier)) [12167863](https://pubmed.ncbi.nlm.nih.gov/12167863). [S2CID](/source/S2CID_(identifier)) [4403228](https://api.semanticscholar.org/CorpusID:4403228).

- 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](/source/Doi_(identifier)):[10.1016/S0022-2836(02)00998-1](https://doi.org/10.1016%2FS0022-2836%2802%2900998-1). [PMID](/source/PMID_(identifier)) [12419264](https://pubmed.ncbi.nlm.nih.gov/12419264).

- Gaddis NC, Chertova E, Sheehy AM, Henderson LE, Malim MH (May 2003). ["Comprehensive investigation of the molecular defect in vif-deficient human immunodeficiency virus type 1 virions"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC154025). *Journal of Virology*. **77** (10): 5810–20. [doi](/source/Doi_(identifier)):[10.1128/JVI.77.10.5810-5820.2003](https://doi.org/10.1128%2FJVI.77.10.5810-5820.2003). [PMC](/source/PMC_(identifier)) [154025](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC154025). [PMID](/source/PMID_(identifier)) [12719574](https://pubmed.ncbi.nlm.nih.gov/12719574).

- Lecossier D, Bouchonnet F, Clavel F, Hance AJ (May 2003). "Hypermutation of HIV-1 DNA in the absence of the Vif protein". *Science*. **300** (5622): 1112. [doi](/source/Doi_(identifier)):[10.1126/science.1083338](https://doi.org/10.1126%2Fscience.1083338). [PMID](/source/PMID_(identifier)) [12750511](https://pubmed.ncbi.nlm.nih.gov/12750511). [S2CID](/source/S2CID_(identifier)) [20591673](https://api.semanticscholar.org/CorpusID:20591673).

- Zhang H, Yang B, Pomerantz RJ, Zhang C, Arunachalam SC, Gao L (Jul 2003). ["The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1350966). *Nature*. **424** (6944): 94–8. [Bibcode](/source/Bibcode_(identifier)):[2003Natur.424...94Z](https://ui.adsabs.harvard.edu/abs/2003Natur.424...94Z). [doi](/source/Doi_(identifier)):[10.1038/nature01707](https://doi.org/10.1038%2Fnature01707). [PMC](/source/PMC_(identifier)) [1350966](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1350966). [PMID](/source/PMID_(identifier)) [12808465](https://pubmed.ncbi.nlm.nih.gov/12808465).

- Mangeat B, Turelli P, Caron G, Friedli M, Perrin L, Trono D (Jul 2003). "Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts". *Nature*. **424** (6944): 99–103. [Bibcode](/source/Bibcode_(identifier)):[2003Natur.424...99M](https://ui.adsabs.harvard.edu/abs/2003Natur.424...99M). [doi](/source/Doi_(identifier)):[10.1038/nature01709](https://doi.org/10.1038%2Fnature01709). [PMID](/source/PMID_(identifier)) [12808466](https://pubmed.ncbi.nlm.nih.gov/12808466). [S2CID](/source/S2CID_(identifier)) [4347374](https://api.semanticscholar.org/CorpusID:4347374).

- Harris RS, Bishop KN, Sheehy AM, Craig HM, Petersen-Mahrt SK, Watt IN, Neuberger MS, Malim MH (Jun 2003). ["DNA deamination mediates innate immunity to retroviral infection"](https://doi.org/10.1016%2FS0092-8674%2803%2900423-9). *Cell*. **113** (6): 803–9. [doi](/source/Doi_(identifier)):[10.1016/S0092-8674(03)00423-9](https://doi.org/10.1016%2FS0092-8674%2803%2900423-9). [PMID](/source/PMID_(identifier)) [12809610](https://pubmed.ncbi.nlm.nih.gov/12809610). [S2CID](/source/S2CID_(identifier)) [544971](https://api.semanticscholar.org/CorpusID:544971).

- 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](/source/Doi_(identifier)):[10.1038/ni0703-641](https://doi.org/10.1038%2Fni0703-641). [PMID](/source/PMID_(identifier)) [12830140](https://pubmed.ncbi.nlm.nih.gov/12830140). [S2CID](/source/S2CID_(identifier)) [5549252](https://api.semanticscholar.org/CorpusID:5549252).

- Gu Y, Sundquist WI (Jul 2003). ["Good to CU"](https://doi.org/10.1038%2F424021a). *Nature*. **424** (6944): 21–2. [Bibcode](/source/Bibcode_(identifier)):[2003Natur.424...21G](https://ui.adsabs.harvard.edu/abs/2003Natur.424...21G). [doi](/source/Doi_(identifier)):[10.1038/424021a](https://doi.org/10.1038%2F424021a). [PMID](/source/PMID_(identifier)) [12840737](https://pubmed.ncbi.nlm.nih.gov/12840737). [S2CID](/source/S2CID_(identifier)) [4430569](https://api.semanticscholar.org/CorpusID:4430569).

- Mariani R, Chen D, Schröfelbauer B, Navarro F, König R, Bollman B, Münk C, Nymark-McMahon H, Landau NR (Jul 2003). ["Species-specific exclusion of APOBEC3G from HIV-1 virions by Vif"](https://doi.org/10.1016%2FS0092-8674%2803%2900515-4). *Cell*. **114** (1): 21–31. [doi](/source/Doi_(identifier)):[10.1016/S0092-8674(03)00515-4](https://doi.org/10.1016%2FS0092-8674%2803%2900515-4). [PMID](/source/PMID_(identifier)) [12859895](https://pubmed.ncbi.nlm.nih.gov/12859895). [S2CID](/source/S2CID_(identifier)) [1789911](https://api.semanticscholar.org/CorpusID:1789911).

v t e Proteasome endopeptidase complex subunits (EC 3.4.25.1) A (alpha subunits) PSMA1 PSMA2 PSMA3 PSMA4 PSMA5 PSMA6 PSMA7 PSMA8 B (beta subunits) PSMB1 PSMB2 PSMB3 PSMB4 PSMB5 PSMB6 PSMB7 PSMB8 PSMB9 PSMB10 C (ATPases) PSMC1 PSMC2 PSMC3 PSMC4 PSMC5 PSMC6 D (non-ATPases) PSMD1 PSMD2 PSMD3 PSMD4 PSMD5 PSMD6 PSMD7 PSMD8 PSMD9 PSMD10 PSMD11 PSMD12 PSMD13 PSMD14 E (activator subunits) PSME1 PSME2 PSME3 PSME4 F (inhibitor subunit) PSMF1

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Adapted from the Wikipedia article [PSMD3](https://en.wikipedia.org/wiki/PSMD3) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/PSMD3?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.