UniProt functional annotation for Q93009



	UniProt functional annotation for Q93009

UniProt code: Q93009.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Hydrolase that deubiquitinates target proteins such as FOXO4, p53/TP53, MDM2, ERCC6, DNMT1, UHRF1, PTEN, KMT2E/MLL5 and DAXX (PubMed:11923872, PubMed:15053880, PubMed:16964248, PubMed:18716620, PubMed:25283148, PubMed:26678539, PubMed:28655758). Together with DAXX, prevents MDM2 self-ubiquitination and enhances the E3 ligase activity of MDM2 towards p53/TP53, thereby promoting p53/TP53 ubiquitination and proteasomal degradation (PubMed:15053880, PubMed:16845383, PubMed:18566590, PubMed:20153724). Deubiquitinates p53/TP53, preventing degradation of p53/TP53, and enhances p53/TP53-dependent transcription regulation, cell growth repression and apoptosis (PubMed:25283148). Deubiquitinates p53/TP53 and MDM2 and strongly stabilizes p53/TP53 even in the presence of excess MDM2, and also induces p53/TP53-dependent cell growth repression and apoptosis (PubMed:11923872). Deubiquitination of FOXO4 in presence of hydrogen peroxide is not dependent on p53/TP53 and inhibits FOXO4-induced transcriptional activity (PubMed:16964248). In association with DAXX, is involved in the deubiquitination and translocation of PTEN from the nucleus to the cytoplasm, both processes that are counteracted by PML (PubMed:18716620). Deubiquitinates KMT2E/MLL5 preventing KMT2E/MLL5 proteasomal-mediated degradation (PubMed:26678539). Involved in cell proliferation during early embryonic development. Involved in transcription-coupled nucleotide excision repair (TC-NER) in response to UV damage: recruited to DNA damage sites following interaction with KIAA1530/UVSSA and promotes deubiquitination of ERCC6, preventing UV- induced degradation of ERCC6 (PubMed:22466611, PubMed:22466612). Involved in maintenance of DNA methylation via its interaction with UHRF1 and DNMT1: acts by mediating deubiquitination of UHRF1 and DNMT1, preventing their degradation and promoting DNA methylation by DNMT1 (PubMed:21745816, PubMed:22411829). Deubiquitinates alkylation repair enzyme ALKBH3. OTUD4 recruits USP7 and USP9X to stabilize ALKBH3, thereby promoting the repair of alkylated DNA lesions (PubMed:25944111). Acts as a chromatin regulator via its association with the Polycomb group (PcG) multiprotein PRC1-like complex; may act by deubiquitinating components of the PRC1-like complex (PubMed:20601937). Able to mediate deubiquitination of histone H2B; it is however unsure whether this activity takes place in vivo (PubMed:20601937). Exhibits a preference towards 'Lys-48'-linked ubiquitin chains (PubMed:22689415). Increases regulatory T-cells (Treg) suppressive capacity by deubiquitinating and stabilizing the transcription factor FOXP3 which is crucial for Treg cell function (PubMed:23973222). Plays a role in the maintenance of the circadian clock periodicity via deubiquitination and stabilization of the CRY1 and CRY2 proteins (PubMed:27123980). Deubiquitinates REST, thereby stabilizing REST and promoting the maintenance of neural progenitor cells (PubMed:21258371). Deubiquitinates SIRT7, inhibiting SIRT7 histone deacetylase activity and regulating gluconeogenesis (PubMed:28655758). {ECO:0000269|PubMed:11923872, ECO:0000269|PubMed:15053880, ECO:0000269|PubMed:16845383, ECO:0000269|PubMed:16964248, ECO:0000269|PubMed:18566590, ECO:0000269|PubMed:18716620, ECO:0000269|PubMed:20153724, ECO:0000269|PubMed:20601937, ECO:0000269|PubMed:21258371, ECO:0000269|PubMed:21745816, ECO:0000269|PubMed:22411829, ECO:0000269|PubMed:22466611, ECO:0000269|PubMed:22466612, ECO:0000269|PubMed:22689415, ECO:0000269|PubMed:23973222, ECO:0000269|PubMed:25283148, ECO:0000269|PubMed:25944111, ECO:0000269|PubMed:26678539, ECO:0000269|PubMed:27123980, ECO:0000269|PubMed:28655758}.

Function: (Microbial infection) Contributes to the overall stabilization and trans-activation capability of the herpesvirus 1 trans-acting transcriptional protein ICP0/VMW110 during HSV-1 infection. {ECO:0000269|PubMed:14506283, ECO:0000269|PubMed:16160161, ECO:0000269|PubMed:18590780}.

Catalytic activity: Reaction=Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76- residue protein attached to proteins as an intracellular targeting signal).; EC=3.4.19.12; Evidence={ECO:0000269|PubMed:11923872, ECO:0000269|PubMed:12507430, ECO:0000269|PubMed:14506283, ECO:0000269|PubMed:15053880, ECO:0000269|PubMed:16964248, ECO:0000269|PubMed:18716620, ECO:0000269|PubMed:21745816, ECO:0000269|PubMed:26678539, ECO:0000269|PubMed:28655758};

Activity regulation: Inhibited by N-ethyl-maleimide (NEM) and divalent cations. Tolerates high concentrations of NaCl but is inhibited at concentrations of 195 mM and higher. {ECO:0000269|PubMed:14506283}.

Biophysicochemical properties: pH dependence: Active from pH 7.0 to 9.5. {ECO:0000269|PubMed:14506283};

Subunit: Monomer. Homodimer. Part of a complex with DAXX, MDM2, RASSF1 and USP7 (PubMed:18566590). Part of a complex with DAXX, MDM2 and USP7 (PubMed:16845383). Interacts with MDM2; the interaction is independent of p53/TP53. Interacts with DAXX; the interaction is direct and independent of MDM2 and p53/TP53 (PubMed:16845383). Component of a complex composed of KMT2E/MLL5 (isoform 3), OGT (isoform 1) and USP7; the complex stabilizes KMT2E/MLL5, preventing KMT2E/MLL5 ubiquitination and proteosomal-mediated degradation (PubMed:26678539). Interacts (via MATH domain) with KMT2E/MLL5 isoform 3 (PubMed:26678539). Interacts with OGT isoform 1 (PubMed:26678539). Interacts with FOXO4; the interaction is enhanced in presence of hydrogen peroxide and occurs independently of p53/TP53 (PubMed:16964248). Interacts with p53/TP53; the interaction is enhanced in response to DNA damage (PubMed:25283148). Interacts with TSPYL5; this impairs interaction with p53/TP53 (PubMed:21170034). Interacts with PTEN; the interaction is direct (PubMed:18716620). Interacts with ATXN1 and the strength of interaction is influenced by the length of the poly-Gln region in ATXN1 (PubMed:12093161). A weaker interaction seen with mutants having longer poly-Gln regions (PubMed:12093161). Interacts with KIAA1530/UVSSA (PubMed:22466611, PubMed:22466612). Interacts with ABRAXAS2; the interaction is direct (PubMed:25283148). Identified in a complex with TP53/p53 and ABRAXAS2 (PubMed:25283148). Interacts with MEX3C and antagonizes its ability to degrade mRNA (PubMed:22863774). Interacts with DNMT1 and UHRF1 (PubMed:21745816, PubMed:22411829). Interacts with FOXP3 (PubMed:23973222). Interacts (via MATH domain) with RNF220. Associated component of the Polycomb group (PcG) multiprotein PRC1-like complex (PubMed:20601937). Interacts with EPOP (By similarity). Interacts with OTUD4 and USP9X; the interaction is direct (PubMed:25944111). Interacts with CRY2 (PubMed:27123980). Interacts with REST (PubMed:21258371). Interacts with ERCC6 (PubMed:26030138). {ECO:0000250|UniProtKB:Q6A4J8, ECO:0000269|PubMed:12093161, ECO:0000269|PubMed:16845383, ECO:0000269|PubMed:16964248, ECO:0000269|PubMed:18566590, ECO:0000269|PubMed:18716620, ECO:0000269|PubMed:20601937, ECO:0000269|PubMed:21170034, ECO:0000269|PubMed:21258371, ECO:0000269|PubMed:21745816, ECO:0000269|PubMed:22411829, ECO:0000269|PubMed:22466611, ECO:0000269|PubMed:22466612, ECO:0000269|PubMed:22863774, ECO:0000269|PubMed:25266658, ECO:0000269|PubMed:25283148, ECO:0000269|PubMed:25944111, ECO:0000269|PubMed:26030138, ECO:0000269|PubMed:26678539, ECO:0000269|PubMed:27123980}.

Subunit: (Microbial infection) Isoform 1 and isoform 2 interact with herpesvirus 1 trans-acting transcriptional protein ICP0/VMW110 (PubMed:9034339, PubMed:14506283, PubMed:16160161, PubMed:18590780). Binding to ICP0/VMW110 may modulate the substrate specificity or activity of USP7 to stabilize viral proteins. {ECO:0000269|PubMed:14506283, ECO:0000269|PubMed:16160161, ECO:0000269|PubMed:18590780, ECO:0000269|PubMed:9034339}.

Subunit: (Microbial infection) Interacts with Epstein-Barr virus EBNA1. EBNA1 shows a 10-fold higher affinity than p53/TP53 and can compete with it for USP7 binding. {ECO:0000269|PubMed:14506283}.

Subcellular location: Nucleus {ECO:0000269|PubMed:21258371, ECO:0000269|PubMed:23973222, ECO:0000269|PubMed:25283148, ECO:0000269|PubMed:26678539}. Cytoplasm {ECO:0000269|PubMed:25283148}. Nucleus, PML body {ECO:0000269|PubMed:9034339}. Chromosome {ECO:0000269|PubMed:20601937}. Note=Present in a minority of ND10 nuclear bodies. Association with ICP0/VMW110 at early times of infection leads to an increased proportion of USP7-containing ND10. Colocalizes with ATXN1 in the nucleus. Colocalized with DAXX in speckled structures. Colocalized with PML and PTEN in promyelocytic leukemia protein (PML) nuclear bodies.

Tissue specificity: Expressed in neural progenitor cells (at protein level) (PubMed:21258371). Widely expressed. Overexpressed in prostate cancer. {ECO:0000269|PubMed:18716620, ECO:0000269|PubMed:21258371}.

Induction: Up-regulated in regulatory T-cells (Treg). Down-regulated during neural progenitor cell differentiation (PubMed:21258371). {ECO:0000269|PubMed:21258371, ECO:0000269|PubMed:23973222}.

Domain: The C-terminus plays a role in its oligomerization. {ECO:0000250}.

Ptm: Isoform 1: Phosphorylated. Isoform 1 is phosphorylated at positions Ser-18 and Ser-963. Isoform 2: Not phosphorylated. {ECO:0000269|PubMed:17651432}.

Ptm: Isoform 1: Polyneddylated. Isoform 2: Not Polyneddylated.

Ptm: Isoform 1 and isoform 2: Not sumoylated.

Ptm: Isoform 1 and isoform 2: Polyubiquitinated by herpesvirus 1 trans- acting transcriptional protein ICP0/VMW110; leading to its subsequent proteasomal degradation. Isoform 1: Ubiquitinated at Lys-869. {ECO:0000269|PubMed:16160161, ECO:0000269|PubMed:17651432}.

Similarity: Belongs to the peptidase C19 family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Hydrolase that deubiquitinates target proteins such as FOXO4, p53/TP53, MDM2, ERCC6, DNMT1, UHRF1, PTEN, KMT2E/MLL5 and DAXX (PubMed:11923872, PubMed:15053880, PubMed:16964248, PubMed:18716620, PubMed:25283148, PubMed:26678539, PubMed:28655758). Together with DAXX, prevents MDM2 self-ubiquitination and enhances the E3 ligase activity of MDM2 towards p53/TP53, thereby promoting p53/TP53 ubiquitination and proteasomal degradation (PubMed:15053880, PubMed:16845383, PubMed:18566590, PubMed:20153724). Deubiquitinates p53/TP53, preventing degradation of p53/TP53, and enhances p53/TP53-dependent transcription regulation, cell growth repression and apoptosis (PubMed:25283148). Deubiquitinates p53/TP53 and MDM2 and strongly stabilizes p53/TP53 even in the presence of excess MDM2, and also induces p53/TP53-dependent cell growth repression and apoptosis (PubMed:11923872). Deubiquitination of FOXO4 in presence of hydrogen peroxide is not dependent on p53/TP53 and inhibits FOXO4-induced transcriptional activity (PubMed:16964248). In association with DAXX, is involved in the deubiquitination and translocation of PTEN from the nucleus to the cytoplasm, both processes that are counteracted by PML (PubMed:18716620). Deubiquitinates KMT2E/MLL5 preventing KMT2E/MLL5 proteasomal-mediated degradation (PubMed:26678539). Involved in cell proliferation during early embryonic development. Involved in transcription-coupled nucleotide excision repair (TC-NER) in response to UV damage: recruited to DNA damage sites following interaction with KIAA1530/UVSSA and promotes deubiquitination of ERCC6, preventing UV- induced degradation of ERCC6 (PubMed:22466611, PubMed:22466612). Involved in maintenance of DNA methylation via its interaction with UHRF1 and DNMT1: acts by mediating deubiquitination of UHRF1 and DNMT1, preventing their degradation and promoting DNA methylation by DNMT1 (PubMed:21745816, PubMed:22411829). Deubiquitinates alkylation repair enzyme ALKBH3. OTUD4 recruits USP7 and USP9X to stabilize ALKBH3, thereby promoting the repair of alkylated DNA lesions (PubMed:25944111). Acts as a chromatin regulator via its association with the Polycomb group (PcG) multiprotein PRC1-like complex; may act by deubiquitinating components of the PRC1-like complex (PubMed:20601937). Able to mediate deubiquitination of histone H2B; it is however unsure whether this activity takes place in vivo (PubMed:20601937). Exhibits a preference towards 'Lys-48'-linked ubiquitin chains (PubMed:22689415). Increases regulatory T-cells (Treg) suppressive capacity by deubiquitinating and stabilizing the transcription factor FOXP3 which is crucial for Treg cell function (PubMed:23973222). Plays a role in the maintenance of the circadian clock periodicity via deubiquitination and stabilization of the CRY1 and CRY2 proteins (PubMed:27123980). Deubiquitinates REST, thereby stabilizing REST and promoting the maintenance of neural progenitor cells (PubMed:21258371). Deubiquitinates SIRT7, inhibiting SIRT7 histone deacetylase activity and regulating gluconeogenesis (PubMed:28655758). {ECO:0000269\|PubMed:11923872, ECO:0000269\|PubMed:15053880, ECO:0000269\|PubMed:16845383, ECO:0000269\|PubMed:16964248, ECO:0000269\|PubMed:18566590, ECO:0000269\|PubMed:18716620, ECO:0000269\|PubMed:20153724, ECO:0000269\|PubMed:20601937, ECO:0000269\|PubMed:21258371, ECO:0000269\|PubMed:21745816, ECO:0000269\|PubMed:22411829, ECO:0000269\|PubMed:22466611, ECO:0000269\|PubMed:22466612, ECO:0000269\|PubMed:22689415, ECO:0000269\|PubMed:23973222, ECO:0000269\|PubMed:25283148, ECO:0000269\|PubMed:25944111, ECO:0000269\|PubMed:26678539, ECO:0000269\|PubMed:27123980, ECO:0000269\|PubMed:28655758}.



Function:		(Microbial infection) Contributes to the overall stabilization and trans-activation capability of the herpesvirus 1 trans-acting transcriptional protein ICP0/VMW110 during HSV-1 infection. {ECO:0000269\|PubMed:14506283, ECO:0000269\|PubMed:16160161, ECO:0000269\|PubMed:18590780}.


Catalytic activity:		Reaction=Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76- residue protein attached to proteins as an intracellular targeting signal).; EC=3.4.19.12; Evidence={ECO:0000269\|PubMed:11923872, ECO:0000269\|PubMed:12507430, ECO:0000269\|PubMed:14506283, ECO:0000269\|PubMed:15053880, ECO:0000269\|PubMed:16964248, ECO:0000269\|PubMed:18716620, ECO:0000269\|PubMed:21745816, ECO:0000269\|PubMed:26678539, ECO:0000269\|PubMed:28655758};
Activity regulation:		Inhibited by N-ethyl-maleimide (NEM) and divalent cations. Tolerates high concentrations of NaCl but is inhibited at concentrations of 195 mM and higher. {ECO:0000269\|PubMed:14506283}.
Biophysicochemical properties:		pH dependence: Active from pH 7.0 to 9.5. {ECO:0000269\|PubMed:14506283};
Subunit:		Monomer. Homodimer. Part of a complex with DAXX, MDM2, RASSF1 and USP7 (PubMed:18566590). Part of a complex with DAXX, MDM2 and USP7 (PubMed:16845383). Interacts with MDM2; the interaction is independent of p53/TP53. Interacts with DAXX; the interaction is direct and independent of MDM2 and p53/TP53 (PubMed:16845383). Component of a complex composed of KMT2E/MLL5 (isoform 3), OGT (isoform 1) and USP7; the complex stabilizes KMT2E/MLL5, preventing KMT2E/MLL5 ubiquitination and proteosomal-mediated degradation (PubMed:26678539). Interacts (via MATH domain) with KMT2E/MLL5 isoform 3 (PubMed:26678539). Interacts with OGT isoform 1 (PubMed:26678539). Interacts with FOXO4; the interaction is enhanced in presence of hydrogen peroxide and occurs independently of p53/TP53 (PubMed:16964248). Interacts with p53/TP53; the interaction is enhanced in response to DNA damage (PubMed:25283148). Interacts with TSPYL5; this impairs interaction with p53/TP53 (PubMed:21170034). Interacts with PTEN; the interaction is direct (PubMed:18716620). Interacts with ATXN1 and the strength of interaction is influenced by the length of the poly-Gln region in ATXN1 (PubMed:12093161). A weaker interaction seen with mutants having longer poly-Gln regions (PubMed:12093161). Interacts with KIAA1530/UVSSA (PubMed:22466611, PubMed:22466612). Interacts with ABRAXAS2; the interaction is direct (PubMed:25283148). Identified in a complex with TP53/p53 and ABRAXAS2 (PubMed:25283148). Interacts with MEX3C and antagonizes its ability to degrade mRNA (PubMed:22863774). Interacts with DNMT1 and UHRF1 (PubMed:21745816, PubMed:22411829). Interacts with FOXP3 (PubMed:23973222). Interacts (via MATH domain) with RNF220. Associated component of the Polycomb group (PcG) multiprotein PRC1-like complex (PubMed:20601937). Interacts with EPOP (By similarity). Interacts with OTUD4 and USP9X; the interaction is direct (PubMed:25944111). Interacts with CRY2 (PubMed:27123980). Interacts with REST (PubMed:21258371). Interacts with ERCC6 (PubMed:26030138). {ECO:0000250\|UniProtKB:Q6A4J8, ECO:0000269\|PubMed:12093161, ECO:0000269\|PubMed:16845383, ECO:0000269\|PubMed:16964248, ECO:0000269\|PubMed:18566590, ECO:0000269\|PubMed:18716620, ECO:0000269\|PubMed:20601937, ECO:0000269\|PubMed:21170034, ECO:0000269\|PubMed:21258371, ECO:0000269\|PubMed:21745816, ECO:0000269\|PubMed:22411829, ECO:0000269\|PubMed:22466611, ECO:0000269\|PubMed:22466612, ECO:0000269\|PubMed:22863774, ECO:0000269\|PubMed:25266658, ECO:0000269\|PubMed:25283148, ECO:0000269\|PubMed:25944111, ECO:0000269\|PubMed:26030138, ECO:0000269\|PubMed:26678539, ECO:0000269\|PubMed:27123980}.
Subunit:		(Microbial infection) Isoform 1 and isoform 2 interact with herpesvirus 1 trans-acting transcriptional protein ICP0/VMW110 (PubMed:9034339, PubMed:14506283, PubMed:16160161, PubMed:18590780). Binding to ICP0/VMW110 may modulate the substrate specificity or activity of USP7 to stabilize viral proteins. {ECO:0000269\|PubMed:14506283, ECO:0000269\|PubMed:16160161, ECO:0000269\|PubMed:18590780, ECO:0000269\|PubMed:9034339}.
Subunit:		(Microbial infection) Interacts with Epstein-Barr virus EBNA1. EBNA1 shows a 10-fold higher affinity than p53/TP53 and can compete with it for USP7 binding. {ECO:0000269\|PubMed:14506283}.
Subcellular location:		Nucleus {ECO:0000269\|PubMed:21258371, ECO:0000269\|PubMed:23973222, ECO:0000269\|PubMed:25283148, ECO:0000269\|PubMed:26678539}. Cytoplasm {ECO:0000269\|PubMed:25283148}. Nucleus, PML body {ECO:0000269\|PubMed:9034339}. Chromosome {ECO:0000269\|PubMed:20601937}. Note=Present in a minority of ND10 nuclear bodies. Association with ICP0/VMW110 at early times of infection leads to an increased proportion of USP7-containing ND10. Colocalizes with ATXN1 in the nucleus. Colocalized with DAXX in speckled structures. Colocalized with PML and PTEN in promyelocytic leukemia protein (PML) nuclear bodies.
Tissue specificity:		Expressed in neural progenitor cells (at protein level) (PubMed:21258371). Widely expressed. Overexpressed in prostate cancer. {ECO:0000269\|PubMed:18716620, ECO:0000269\|PubMed:21258371}.
Induction:		Up-regulated in regulatory T-cells (Treg). Down-regulated during neural progenitor cell differentiation (PubMed:21258371). {ECO:0000269\|PubMed:21258371, ECO:0000269\|PubMed:23973222}.
Domain:		The C-terminus plays a role in its oligomerization. {ECO:0000250}.
Ptm:		Isoform 1: Phosphorylated. Isoform 1 is phosphorylated at positions Ser-18 and Ser-963. Isoform 2: Not phosphorylated. {ECO:0000269\|PubMed:17651432}.
Ptm:		Isoform 1: Polyneddylated. Isoform 2: Not Polyneddylated.
Ptm:		Isoform 1 and isoform 2: Not sumoylated.
Ptm:		Isoform 1 and isoform 2: Polyubiquitinated by herpesvirus 1 trans- acting transcriptional protein ICP0/VMW110; leading to its subsequent proteasomal degradation. Isoform 1: Ubiquitinated at Lys-869. {ECO:0000269\|PubMed:16160161, ECO:0000269\|PubMed:17651432}.
Similarity:		Belongs to the peptidase C19 family. {ECO:0000305}.