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Overview

Uniprot IDQ9Y6I4
Protein NameUbiquitin carboxyl-terminal hydrolase 3
Gene NameUSP3
OrganismHomo sapiens

Kla Sites from experimental identification

Position Flanking peptide
135 ADRHKKRKLLENSTL
145 ENSTLNSKLLKVNGS
148 TLNSKLLKVNGSTTA
354 QFRSKRSKNQENGPV

Function

Deubiquitinase that plays a role in several cellular processes including transcriptional regulation, cell cycle progression or innate immunity. In response to DNA damage, deubiquitinates monoubiquitinated target proteins such as histone H2A and H2AX and thereby counteracts RNF168- and RNF8-mediated ubiquitination. In turn, participates in the recruitment of DNA damage repair factors to DNA break sites (PubMed:24196443). Required for proper progression through S phase and subsequent mitotic entry (PubMed:17980597). Acts as a positive regulator of TP53 by deubiquitinating and stabilizing it to promote normal cell proliferation and transformation (PubMed:28807825). Participates in establishing tolerance innate immune memory through non-transcriptional feedback. Mechanistically, negatively regulates TLR-induced NF-kappa-B signaling by targeting and removing the 'Lys-63'-linked polyubiquitin chains on MYD88 (PubMed:37971847). Negatively regulates the activation of type I interferon signaling by mediating 'Lys-63'-linked polyubiquitin chains on RIGI and IFIH1 (PubMed:24366338). Also deubiquitinates ASC/PYCARD, the central adapter mediating the assembly and activation of most inflammasomes, and thereby promotes inflammasome activation (PubMed:36050480)

Protein Sequence

10 MECPHLSSSV 20 CIAPDSAKFP 30 NGSPSSWCCS 40 VCRSNKSPWV 50 CLTCSSVHCG 60 RYVNGHAKKH 70 YEDAQVPLTN 80 HKKSEKQDKV 90 QHTVCMDCSS 100 YSTYCYRCDD 110 FVVNDTKLGL 120 VQKVREHLQN 130 LENSAFTADR 140 HKKRKLLENS 150 TLNSKLLKVN 160 GSTTAICATG 170 LRNLGNTCFM 180 NAILQSLSNI 190 EQFCCYFKEL 200 PAVELRNGKT 210 AGRRTYHTRS 220 QGDNNVSLVE 230 EFRKTLCALW 240 QGSQTAFSPE 250 SLFYVVWKIM 260 PNFRGYQQQD 270 AHEFMRYLLD 280 HLHLELQGGF 290 NGVSRSAILQ 300 ENSTLSASNK 310 CCINGASTVV 320 TAIFGGILQN 330 EVNCLICGTE 340 SRKFDPFLDL 350 SLDIPSQFRS 360 KRSKNQENGP 370 VCSLRDCLRS 380 FTDLEELDET 390 ELYMCHKCKK 400 KQKSTKKFWI 410 QKLPKVLCLH 420 LKRFHWTAYL 430 RNKVDTYVEF 440 PLRGLDMKCY 450 LLEPENSGPE 460 SCLYDLAAVV 470 VHHGSGVGSG 480 HYTAYATHEG 490 RWFHFNDSTV 500 TLTDEETVVK 510 AKAYILFYVE 520 HQAKAGSDKL

Gene Ontology

Classification GO ID Description
Cellular Component GO:0000785 chromatin
Cellular Component GO:0005737 cytoplasm
Cellular Component GO:0005654 nucleoplasm
Cellular Component GO:0005634 nucleus
Molecular Function GO:0004843 cysteine-type deubiquitinase activity
Molecular Function GO:0042393 histone binding
Molecular Function GO:0140950 histone H2A deubiquitinase activity
Molecular Function GO:0140936 histone H2B deubiquitinase activity
Molecular Function GO:0008270 zinc ion binding
Biological Process GO:0006281 DNA repair
Biological Process GO:0140861 DNA repair-dependent chromatin remodeling
Biological Process GO:0016579 protein deubiquitination
Biological Process GO:0006508 proteolysis

Reference

[1] Yang D, Yin J, Shan L, Yi X, Zhang W et al.. Identification of lysine-lactylated substrates in gastric cancer cells.. iScience 25(7):104630. 2022 Jul 15. PMID: 35800753.

[2] Yang Z, Yan C, Ma J, Peng P, Ren X et al.. Lactylome analysis suggests lactylation-dependent mechanisms of metabolic adaptation in hepatocellular carcinoma.. Nat Metab 5(1):61-79. 2023 Jan. PMID: 36593272.

[3] He C, Zhang J, Bai X, Lu C, Zhang K. Lysine lactylation-based insight to understanding the characterization of cervical cancer.. Biochim Biophys Acta Mol Basis Dis 1870(7):167356. 2024 Oct. PMID: 39025375.

[4] He J, Lai T, Zhou Z, Yang H, Lei Z et al.. Multiomics profiling reveals the involvement of protein lactylation in nonhomologous end joining pathway conferring radioresistance in lung adenocarcinoma cell.. Sci Rep 15(1):24651. 2025 Jul 9. PMID: 40634431.

[5] Wu Q, Li Z, Gong T, Zheng X, Zhou X et al.. Porphyromonas gingivalis infection induces lysine lactylation reprogramming in human umbilical vein endothelial cells.. Front Cell Infect Microbiol 16:1706727. 2026. PMID: 41696360.