PSMD14

PSMD14
Identifiers
Aliases	PSMD14, PAD1, POH1, RPN11, proteasome 26S subunit, non-ATPase 14
External IDs	OMIM: 607173; MGI: 1913284; HomoloGene: 4240; GeneCards: PSMD14; OMA:PSMD14 - orthologs
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2q24.2 Start 161,308,425 bp[1] End 161,411,717 bp[1]
Gene location (Mouse) Chr. Chromosome 2 (mouse)[2] Band 2|2 C1.3 Start 61,542,038 bp[2] End 61,630,720 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in middle temporal gyrus endothelial cell deltoid muscle glutes tibialis anterior muscle triceps brachii muscle biceps brachii Skeletal muscle tissue of biceps brachii Brodmann area 23 gingival epithelium Top expressed in endothelial cell of lymphatic vessel primitive streak medial ganglionic eminence facial motor nucleus hair follicle renal corpuscle otic placode Paneth cell condyle vestibular membrane of cochlear duct More reference expression data BioGPS More reference expression data
Gene ontology Molecular function metal ion binding endopeptidase activator activity proteasome binding peptidase activity protein binding hydrolase activity metallopeptidase activity thiol-dependent deubiquitinase Lys63-specific deubiquitinase activity Cellular component cytosol proteasome accessory complex nucleoplasm cytosolic proteasome complex proteasome regulatory particle, lid subcomplex proteasome complex extracellular exosome nucleus extracellular region secretory granule lumen ficolin-1-rich granule lumen Biological process regulation of proteasomal protein catabolic 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 proteolysis cellular response to DNA damage stimulus Fc-epsilon receptor signaling pathway protein K63-linked deubiquitination NIK/NF-kappaB signaling double-strand break repair via homologous recombination anaphase-promoting complex-dependent catabolic process response to ethanol double-strand break repair via nonhomologous end joining T cell receptor signaling pathway negative regulation of canonical Wnt signaling pathway DNA repair positive regulation of endopeptidase activity 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 interleukin-1-mediated signaling pathway regulation of mitotic cell cycle phase transition Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 10213 59029 Ensembl ENSG00000115233 ENSMUSG00000026914 UniProt O00487 O35593 RefSeq (mRNA) NM_005805 NM_021526 RefSeq (protein) NP_005796 NP_067501 Location (UCSC) Chr 2: 161.31 – 161.41 Mb Chr 2: 61.54 – 61.63 Mb PubMed search [3] [4]
Wikidata
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26S proteasome non-ATPase regulatory subunit 14, also known as 26S proteasome non-ATPase subunit Rpn11, is an enzyme that in humans is encoded by the PSMD14 gene.^[5][6] This protein is one of the 19 essential subunits of the complete assembled 19S proteasome complex.^[7] Nine subunits Rpn3, Rpn5, Rpn6, Rpn7, Rpn8, Rpn9, Rpn11, SEM1 (yeast analogue for human protein DSS1), and Rpn12 form the lid sub complex of the 19S regulatory particle of the proteasome complex.^[7]

Gene

The gene PSMD14 encodes one of 26S proteasome non-ATPase subunit.^[6] The human gene PSMD14 has 12 Exons and locates at chromosome band 2q24.2.

Protein

The human protein 26S proteasome non-ATPase regulatory subunit 14 is 34.6 kDa in size and composed of 310 amino acids. The calculated theoretical pI of this protein is 6.06.^[8]

Complex assembly

The 26S proteasome complex usually consists of a 20S core particle (CP, or 20S proteasome) and one or two 19S regulatory particles (RP, or 19S proteasome) on either or both sides of the barrel-shaped 20S subunit. The CP and RPs have distinct structural characteristics and biological functions. Briefly, the 20S subunit has three types of proteolytic activity, including caspase-like, trypsin-like, and chymotrypsin-like activities. These proteolytic active sites are located in the inner side of a chamber formed by 4 stacked rings of 20S subunits, preventing random protein-enzyme encounter and uncontrolled protein degradation. The 19S regulatory particles can recognize ubiquitin-labeled protein as a substrate for degradation, unfold the protein to a linear molecule, open the "gates" of the 20S core particle, and guide the substrate into the proteolytic chamber. To achieve such functional complexity, the 19S regulatory particle contains at least 18 constitutive subunits. These subunits can be categorized into two classes based on their ATP dependence, with both ATP-dependent subunits and ATP-independent subunits. According to the protein interaction and topological characteristics of this multisubunit complex, the 19S regulatory particle is composed of a base and a lid subcomplex. The base consists of a ring of six AAA ATPases (Subunit Rpt1-6, systematic nomenclature) and four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13). The lid sub-complex of the 19S regulatory particle consists of 9 subunits. The assembly of the 19S lid is independent of the assembly process of the 19S base. The two assembly modules, the Rpn5-Rpn6-Rpn8-Rpn9-Rpn11 module and the Rpn3-Rpn7-SEM1 module were identified as playing a role in 19S lid assembly by using the yeast proteasome as a model complex.^{[9][10][11][12]} The subunit Rpn12 incorporated into 19S regulatory particle when 19S lid and base bind together.^[13] Among these lid subunits, protein Rpn11 presents the metalloproteases activity to hydrolyze the ubiquitin molecules from the poly-ubiquitin chain before protein substrates are unfolded and degraded.^[14][15] During substrate degradation, the 19S regulatory particles undergo a conformation switch that is characterized by a rearranged ATPase ring with uniform subunit interfaces. Notably, Rpn11 migrates from an occluded position to directly above the central pore, thus facilitating substrate deubiquitination concomitant with translocation.^[16]

Function

As the degradation machinery that is responsible for ~70% of intracellular proteolysis,^[17] the proteasome complex (26S proteasome) plays critical roles in maintaining the homeostasis of the cellular proteome. Misfolded proteins and damaged protein need to be continuously removed to recycle amino acids for new synthesis; in addition, some key regulatory proteins fulfil their biological functions via selective degradation; furthermore, proteins are digested into peptides for MHC class I antigen presentation. To meet such complicated demands in biological processes via spatial and temporal proteolysis, protein substrates have to be recognized, recruited, and eventually hydrolyzed in a controlled fashion. Thus, the 19S regulatory particle has a series of important capabilities to address these functional challenges. To recognize proteins as designated substrates, the 19S complex has subunits that are capable of recognizing proteins with a special degradative tag, ubiquitination. It also has subunits that can bind to nucleotides (e.g., ATPs) in order to facilitate the association between the 19S and 20S particles, as well as to cause conformational changes to the alpha subunit C-terminals that form the substrate entrance of the 20S complex. Rpn11 drives metalloprotease activity to hydrolyze the ubiquitin molecules from the poly-ubiquitin chain before protein substrates are unfolded and degraded^[14]

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, the proteasome has been considered 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 of the Ubiquitin-Proteasome System (UPS)^[18] 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.^[19] 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,^[20][21] cardiovascular diseases,^[22][23][24] inflammatory responses and autoimmune diseases,^[25] and systemic DNA damage responses leading to malignancies.^[26]

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,^[27] Parkinson's disease^[28] and Pick's disease,^[29] Amyotrophic lateral sclerosis (ALS),^[29] Huntington's disease,^[28] Creutzfeldt–Jakob disease,^[30] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies^[31] and several rare forms of neurodegenerative diseases associated with dementia.^[32] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,^[33] ventricular hypertrophy^[34] and Heart failure.^[35] 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.^[36] 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).^[25] 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.^[37] Lastly, autoimmune disease patients with SLE, Sjögren syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.^[38]

References

1. GRCh38: Ensembl release 89: ENSG00000115233 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000026914 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Spataro V, Toda T, Craig R, Seeger M, Dubiel W, Harris AL, Norbury C (Nov 1997). "Resistance to diverse drugs and ultraviolet light conferred by overexpression of a novel human 26 S proteasome subunit". The Journal of Biological Chemistry. 272 (48): 30470–5. doi:10.1074/jbc.272.48.30470. PMID 9374539.
6. "Entrez Gene: PSMD14 proteasome (prosome, macropain) 26S subunit, non-ATPase, 14".
7. Gu ZC, Enenkel C (Dec 2014). "Proteasome assembly". Cellular and Molecular Life Sciences. 71 (24): 4729–45. doi:10.1007/s00018-014-1699-8. PMC 11113775. PMID 25107634. S2CID 15661805.
8. "Uniprot: O00487 - PSDE_HUMAN".
9. Le Tallec B, Barrault MB, Guérois R, Carré T, Peyroche A (Feb 2009). "Hsm3/S5b participates in the assembly pathway of the 19S regulatory particle of the proteasome". Molecular Cell. 33 (3): 389–99. doi:10.1016/j.molcel.2009.01.010. PMID 19217412.
10. Gödderz D, Dohmen RJ (Feb 2009). "Hsm3/S5b joins the ranks of 26S proteasome assembly chaperones". Molecular Cell. 33 (4): 415–6. doi:10.1016/j.molcel.2009.02.007. PMID 19250902.
11. Isono E, Nishihara K, Saeki Y, Yashiroda H, Kamata N, Ge L, Ueda T, Kikuchi Y, Tanaka K, Nakano A, Toh-e A (Feb 2007). "The assembly pathway of the 19S regulatory particle of the yeast 26S proteasome". Molecular Biology of the Cell. 18 (2): 569–80. doi:10.1091/mbc.E06-07-0635. PMC 1783769. PMID 17135287.
12. Fukunaga K, Kudo T, Toh-e A, Tanaka K, Saeki Y (Jun 2010). "Dissection of the assembly pathway of the proteasome lid in Saccharomyces cerevisiae". Biochemical and Biophysical Research Communications. 396 (4): 1048–53. doi:10.1016/j.bbrc.2010.05.061. PMID 20471955.
13. Tomko RJ, Hochstrasser M (Dec 2011). "Incorporation of the Rpn12 subunit couples completion of proteasome regulatory particle lid assembly to lid-base joining". Molecular Cell. 44 (6): 907–17. doi:10.1016/j.molcel.2011.11.020. PMC 3251515. PMID 22195964.
14. Verma R, Aravind L, Oania R, McDonald WH, Yates JR, Koonin EV, Deshaies RJ (Oct 2002). "Role of Rpn11 metalloprotease in deubiquitination and degradation by the 26S proteasome". Science. 298 (5593): 611–5. Bibcode:2002Sci...298..611V. doi:10.1126/science.1075898. PMID 12183636. S2CID 35369850.
15. Lam YA, Xu W, DeMartino GN, Cohen RE (Feb 1997). "Editing of ubiquitin conjugates by an isopeptidase in the 26S proteasome". Nature. 385 (6618): 737–40. Bibcode:1997Natur.385..737L. doi:10.1038/385737a0. PMID 9034192. S2CID 4349219.
16. Matyskiela ME, Lander GC, Martin A (Jul 2013). "Conformational switching of the 26S proteasome enables substrate degradation". Nature Structural & Molecular Biology. 20 (7): 781–8. doi:10.1038/nsmb.2616. PMC 3712289. PMID 23770819.
17. 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:10.1016/s0092-8674(94)90462-6. PMID 8087844. S2CID 22262916.
18. Kleiger G, Mayor T (Jun 2014). "Perilous journey: a tour of the ubiquitin-proteasome system". Trends in Cell Biology. 24 (6): 352–9. doi:10.1016/j.tcb.2013.12.003. PMC 4037451. PMID 24457024.
19. Goldberg AL, Stein R, Adams J (Aug 1995). "New insights into proteasome function: from archaebacteria to drug development". Chemistry & Biology. 2 (8): 503–8. doi:10.1016/1074-5521(95)90182-5. PMID 9383453.
20. Sulistio YA, Heese K (Jan 2015). "The Ubiquitin-Proteasome System and Molecular Chaperone Deregulation in Alzheimer's Disease". Molecular Neurobiology. 53 (2): 905–31. doi:10.1007/s12035-014-9063-4. PMID 25561438. S2CID 14103185.
21. Ortega Z, Lucas JJ (2014). "Ubiquitin-proteasome system involvement in Huntington's disease". Frontiers in Molecular Neuroscience. 7: 77. doi:10.3389/fnmol.2014.00077. PMC 4179678. PMID 25324717.
22. Sandri M, Robbins J (Jun 2014). "Proteotoxicity: an underappreciated pathology in cardiac disease". Journal of Molecular and Cellular Cardiology. 71: 3–10. doi:10.1016/j.yjmcc.2013.12.015. PMC 4011959. PMID 24380730.
23. Drews O, Taegtmeyer H (Dec 2014). "Targeting the ubiquitin-proteasome system in heart disease: the basis for new therapeutic strategies". Antioxidants & Redox Signaling. 21 (17): 2322–43. doi:10.1089/ars.2013.5823. PMC 4241867. PMID 25133688.
24. Wang ZV, Hill JA (Feb 2015). "Protein quality control and metabolism: bidirectional control in the heart". Cell Metabolism. 21 (2): 215–26. doi:10.1016/j.cmet.2015.01.016. PMC 4317573. PMID 25651176.
25. Karin M, Delhase M (Feb 2000). "The I kappa B kinase (IKK) and NF-kappa B: key elements of proinflammatory signalling". Seminars in Immunology. 12 (1): 85–98. doi:10.1006/smim.2000.0210. PMID 10723801.
26. Ermolaeva MA, Dakhovnik A, Schumacher B (Sep 2015). "Quality control mechanisms in cellular and systemic DNA damage responses". Ageing Research Reviews. 23 (Pt A): 3–11. doi:10.1016/j.arr.2014.12.009. PMC 4886828. PMID 25560147.
27. Checler F, da Costa CA, Ancolio K, Chevallier N, Lopez-Perez E, Marambaud P (Jul 2000). "Role of the proteasome in Alzheimer's disease". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1502 (1): 133–8. doi:10.1016/s0925-4439(00)00039-9. PMID 10899438.
28. Chung KK, Dawson VL, Dawson TM (Nov 2001). "The role of the ubiquitin-proteasomal pathway in Parkinson's disease and other neurodegenerative disorders". Trends in Neurosciences. 24 (11 Suppl): S7–14. doi:10.1016/s0166-2236(00)01998-6. PMID 11881748. S2CID 2211658.
29. Ikeda K, Akiyama H, Arai T, Ueno H, Tsuchiya K, Kosaka K (Jul 2002). "Morphometrical reappraisal of motor neuron system of Pick's disease and amyotrophic lateral sclerosis with dementia". Acta Neuropathologica. 104 (1): 21–8. doi:10.1007/s00401-001-0513-5. PMID 12070660. S2CID 22396490.
30. Manaka H, Kato T, Kurita K, Katagiri T, Shikama Y, Kujirai K, Kawanami T, Suzuki Y, Nihei K, Sasaki H (May 1992). "Marked increase in cerebrospinal fluid ubiquitin in Creutzfeldt–Jakob disease". Neuroscience Letters. 139 (1): 47–9. doi:10.1016/0304-3940(92)90854-z. PMID 1328965. S2CID 28190967.
31. Mathews KD, Moore SA (Jan 2003). "Limb-girdle muscular dystrophy". Current Neurology and Neuroscience Reports. 3 (1): 78–85. doi:10.1007/s11910-003-0042-9. PMID 12507416. S2CID 5780576.
32. Mayer RJ (Mar 2003). "From neurodegeneration to neurohomeostasis: the role of ubiquitin". Drug News & Perspectives. 16 (2): 103–8. doi:10.1358/dnp.2003.16.2.829327. PMID 12792671.
33. Calise J, Powell SR (Feb 2013). "The ubiquitin proteasome system and myocardial ischemia". American Journal of Physiology. Heart and Circulatory Physiology. 304 (3): H337–49. doi:10.1152/ajpheart.00604.2012. PMC 3774499. PMID 23220331.
34. Predmore JM, Wang P, Davis F, Bartolone S, Westfall MV, Dyke DB, Pagani F, Powell SR, Day SM (Mar 2010). "Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies". Circulation. 121 (8): 997–1004. doi:10.1161/CIRCULATIONAHA.109.904557. PMC 2857348. PMID 20159828.
35. Powell SR (Jul 2006). "The ubiquitin-proteasome system in cardiac physiology and pathology". American Journal of Physiology. Heart and Circulatory Physiology. 291 (1): H1 – H19. doi:10.1152/ajpheart.00062.2006. PMID 16501026. S2CID 7073263.
36. Adams J (Apr 2003). "Potential for proteasome inhibition in the treatment of cancer". Drug Discovery Today. 8 (7): 307–15. doi:10.1016/s1359-6446(03)02647-3. PMID 12654543.
37. Ben-Neriah Y (Jan 2002). "Regulatory functions of ubiquitination in the immune system". Nature Immunology. 3 (1): 20–6. doi:10.1038/ni0102-20. PMID 11753406. S2CID 26973319.
38. Egerer K, Kuckelkorn U, Rudolph PE, Rückert JC, Dörner T, Burmester GR, Kloetzel PM, Feist E (Oct 2002). "Circulating proteasomes are markers of cell damage and immunologic activity in autoimmune diseases". The Journal of Rheumatology. 29 (10): 2045–52. PMID 12375310.

Further reading

• Ambroggio XI, Rees DC, Deshaies RJ (Jan 2004). "JAMM: a metalloprotease-like zinc site in the proteasome and signalosome". PLOS Biology. 2 (1): E2. doi:10.1371/journal.pbio.0020002. PMC 300881. PMID 14737182.
• Rush J, Moritz A, Lee KA, Guo A, Goss VL, Spek EJ, Zhang H, Zha XM, Polakiewicz RD, Comb MJ (Jan 2005). "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells". Nature Biotechnology. 23 (1): 94–101. doi:10.1038/nbt1046. PMID 15592455. S2CID 7200157.
• Nabhan JF, Ribeiro P (Jun 2006). "The 19 S proteasomal subunit POH1 contributes to the regulation of c-Jun ubiquitination, stability, and subcellular localization". The Journal of Biological Chemistry. 281 (23): 16099–107. doi:10.1074/jbc.M512086200. PMID 16569633.
• Gallery M, Blank JL, Lin Y, Gutierrez JA, Pulido JC, Rappoli D, Badola S, Rolfe M, Macbeth KJ (Jan 2007). "The JAMM motif of human deubiquitinase Poh1 is essential for cell viability". Molecular Cancer Therapeutics. 6 (1): 262–8. doi:10.1158/1535-7163.MCT-06-0542. PMID 17237285. S2CID 13102406.
• Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology. 3 (1): 89. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931.

External links

• PSMD14 human gene location in the UCSC Genome Browser.
• PSMD14 human gene details in the UCSC Genome Browser.