Ubiquitin C-terminal hydrolase PSMD14

Function

Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. The PSMD14 subunit is a metalloprotease that specifically cleaves 'Lys-63'-linked polyubiquitin chains within the complex. Plays a role in response to double-strand breaks (DSBs): acts as a regulator of non-homologous end joining (NHEJ) by cleaving 'Lys-63'-linked polyubiquitin, thereby promoting retention of JMJD2A/KDM4A on chromatin and restricting TP53BP1 accumulation. Also involved in homologous recombination repair by promoting RAD51 loading. Regulates macroautophagy by ensuring Golgi-to-ER retrograde transport through its deubiquitinating activity on K63-linked ubiquitin chains. This activity prevents the retention of essential autophagy proteins at the Golgi, enabling their trafficking to autophagosome formation sites and supporting Golgi-ER membrane recycling critical for effective autophagy.

Classification

Family (Pfam)

PF01398 JAB, PF23594 RPN11_C

InterPro

JAMM/MPN+_dom, JAMM_MPN+_peptidase_M67A, MPN, RPN11_C

Functional cluster

Protein Serine/Threonine Kinases

Experimental structures · PDB · 79

• 5GJQ EM 4.50A
• 5GJR EM 3.50A
• 5L4K EM 4.50A
• 5LN3 EM 6.80A
• 5M32 EM 3.80A
• 5T0C EM 3.80A
• 5T0G EM 4.40A
• 5T0H EM 6.80A
• 5T0I EM 8.00A
• 5T0J EM 8.00A
• 5VFP EM 4.20A
• 5VFQ EM 4.20A
• … and 67 more

A predicted model is available from AlphaFold.

Gene Ontology · 32

• GO:0005829 cytosol
• GO:0031597 cytosolic proteasome complex
• GO:0005576 extracellular region
• GO:1904813 ficolin-1-rich granule lumen
• GO:0005654 nucleoplasm
• GO:0005634 nucleus
• GO:0022624 proteasome accessory complex
• GO:0000502 proteasome complex
• GO:0008541 proteasome regulatory particle, lid subcomplex
• GO:0034774 secretory granule lumen
• GO:0008021 synaptic vesicle
• GO:0004843 cysteine-type deubiquitinase activity
• GO:0061133 endopeptidase activator activity
• GO:0061578 K63-linked deubiquitinase activity
• GO:0046872 metal ion binding
• GO:0140492 metal-dependent deubiquitinase activity
• GO:0008237 metallopeptidase activity
• GO:0070628 proteasome binding
• GO:0006914 autophagy
• GO:0071357 cellular response to type I interferon
• GO:0000724 double-strand break repair via homologous recombination
• GO:0006303 double-strand break repair via nonhomologous end joining
• GO:0010498 proteasomal protein catabolic process
• GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process
• GO:0016579 protein deubiquitination
• GO:0070536 protein K63-linked deubiquitination
• GO:0016241 regulation of macroautophagy
• GO:0061136 regulation of proteasomal protein catabolic process
• GO:0045471 response to ethanol
• GO:0006979 response to oxidative stress
• GO:0006890 retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum
• GO:0006511 ubiquitin-dependent protein catabolic process

Drugs targeting this protein · 6

• OPROZOMIB inhibitor
• IXAZOMIB inhibitor
• BORTEZOMIB inhibitor
• IXAZOMIB CITRATE inhibitor
• CARFILZOMIB inhibitor
• BORTEZOMIB D-MANNITOL inhibitor

Related proteins · sequence + function similarity

• 26S proteasome non-ATPase regulatory subunit 14 0.97
• 26S proteasome regulatory subunit rpn11 0.96
• 26S proteasome non-ATPase regulatory subunit 14 homolog 0.95
• 26S proteasome non-ATPase regulatory subunit 14 0.95
• Ubiquitin C-terminal hydrolase RPN11 0.92
• 26S proteasome regulatory subunit RPN11 0.91
• 26S proteasome regulatory subunit RPN11 0.91
• 26S proteasome regulatory subunit RPN11 0.90
• Uncharacterized protein F37A4.5 0.88
• 26S proteasome non-ATPase regulatory subunit 14 0.88
• COP9 signalosome complex subunit 5 0.84
• COP9 signalosome complex subunit 5 0.84

Co-cited proteins · studied together in the literature

• Thioredoxin-like protein 1 1 shared papers
• 26S proteasome non-ATPase regulatory subunit 6 3 shared papers
• BRISC and BRCA1-A complex member 1 1 shared papers
• 26S proteasome non-ATPase regulatory subunit 13 3 shared papers
• 26S proteasome non-ATPase regulatory subunit 7 3 shared papers
• BRISC complex subunit Abraxas 2 1 shared papers
• BRISC and BRCA1-A complex member 2 1 shared papers
• 26S proteasome non-ATPase regulatory subunit 12 3 shared papers
• 26S proteasome non-ATPase regulatory subunit 8 3 shared papers
• 26S proteasome regulatory subunit 10B 3 shared papers
• 26S proteasome non-ATPase regulatory subunit 2 3 shared papers
• 26S proteasome non-ATPase regulatory subunit 11 3 shared papers

Literature · 16 cited papers

• The Proteasomal Deubiquitinating Enzyme PSMD14 Regulates Macroautophagy by Controlling Golgi-to-ER Retrograde Transport. Cells · 2020
• An atomic structure of the human 26S proteasome. Nat. Struct. Mol. Biol. · 2016
• Structure of the human 26S proteasome at a resolution of 3.9 Aa. Proc. Natl. Acad. Sci. U.S.A. · 2016
• An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J. Proteomics · 2014
• Toward a comprehensive characterization of a human cancer cell phosphoproteome. J. Proteome Res. · 2013
• The proteasomal de-ubiquitinating enzyme POH1 promotes the double-strand DNA break response. EMBO J. · 2012
• Initial characterization of the human central proteome. BMC Syst. Biol. · 2011
• Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions. Sci. Signal. · 2009
• Thioredoxin Txnl1/TRP32 is a redox-active cofactor of the 26 S proteasome. J. Biol. Chem. · 2009
• K63-specific deubiquitination by two JAMM/MPN+ complexes: BRISC-associated Brcc36 and proteasomal Poh1. EMBO J. · 2009
• Quantitative phosphoproteome profiling of Wnt3a-mediated signaling network: indicating the involvement of ribonucleoside-diphosphate reductase M2 subunit phosphorylation at residue serine 20 in canonical Wnt signal transduction. Mol. Cell. Proteomics · 2007
• Mass spectrometric characterization of the affinity-purified human 26S proteasome complex. Biochemistry · 2007
• … and 4 more in the literature graph