UniProt functional annotation for P40818



	UniProt functional annotation for P40818

UniProt code: P40818.

Organism: Homo sapiens (Human).

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

Function: Hydrolase that can remove conjugated ubiquitin from proteins and therefore plays an important regulatory role at the level of protein turnover by preventing degradation. Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains. Catalytic activity is enhanced in the M phase. Involved in cell proliferation. Required to enter into S phase in response to serum stimulation. May regulate T-cell anergy mediated by RNF128 via the formation of a complex containing RNF128 and OTUB1. Probably regulates the stability of STAM2 and RASGRF1. Regulates endosomal ubiquitin dynamics, cargo sorting, membrane traffic at early endosomes, and maintenance of ESCRT-0 stability. The level of protein ubiquitination on endosomes is essential for maintaining the morphology of the organelle. Deubiquitinates EPS15 and controles tyrosine kinase stability. Removes conjugated ubiquitin from EGFR thus regulating EGFR degradation and downstream MAPK signaling. Involved in acrosome biogenesis through interaction with the spermatid ESCRT-0 complex and microtubules. Deubiquitinates BIRC6/bruce and KIF23/MKLP1. Deubiquitinates BACE1 which inhibits BACE1 lysosomal degradation and modulates BACE-mediated APP cleavage and amyloid-beta formation (PubMed:27302062). {ECO:0000269|PubMed:16520378, ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:18329369, ECO:0000269|PubMed:27302062, ECO:0000269|PubMed:9628861}.

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:9628861};

Subunit: Forms a ternary complex with RNF128 and OTUB1. Interacts (via C-terminal UCH catalytic domain) with OTUB1 isoform 1. Interacts with STAM2 (via SH3 domain). Interacts with DNAJB3, EGFR, EPS15, RASGRF1, RNF41, YWHAE, YWHAG and YWHAZ (By similarity). Interacts with NBR1, RASGRF1, RNF41 and IST1. Associates with the ESCRT-0 complex and with microtubules (By similarity). Interacts with BIRC6/bruce and KIF23/MKLP1. {ECO:0000250, ECO:0000269|PubMed:17035239, ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:18329369, ECO:0000269|PubMed:19129480, ECO:0000269|PubMed:19427866}.

Subunit: (Microbial infection) Interacts with Zika virus non-structural protein 1. {ECO:0000269|PubMed:30065070}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:16520378, ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:19427866, ECO:0000269|PubMed:28505279}. Nucleus {ECO:0000250|UniProtKB:Q80U87}. Endosome membrane {ECO:0000269|PubMed:16520378, ECO:0000269|PubMed:17711858}; Peripheral membrane protein {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:16520378}; Peripheral membrane protein {ECO:0000305}.

Induction: Upon growth stimulation in starved human fibroblasts. Decreases in response to growth arrest induced by cell-cell contact. {ECO:0000269|PubMed:9628861}.

Domain: The MIT domain is required for endosomal localization, CHMP1B- binding, maintenance of ESCRT-0 stability and EGFR degradation. {ECO:0000269|PubMed:17711858}.

Domain: The rhodanese domain is sufficient for RNF41-binding. {ECO:0000250}.

Ptm: Phosphorylation of Ser-718 is essential for interaction with YWHAE and for cytosol localization. Undergoes dephosphorylation at Ser-718 in the M phase. Tyrosine-phosphorylated in its N-terminal half in an EGFR- dependent manner. {ECO:0000250}.

Ptm: Ubiquitinated. Inactive form is mostly monoubiquitinated, but polyubiquitination happens too. Ubiquitination is increased in EGF- stimulated cells. Ubiquitination of active form is undetectable, suggesting a possibility that USP8 deubiquitinates itself, thereby regulating its own function (By similarity). {ECO:0000250}.

Disease: Pituitary adenoma 4, ACTH-secreting (PITA4) [MIM:219090]: A form of pituitary adenoma, a neoplasm of the pituitary gland and one of the most common neuroendocrine tumors. Pituitary adenomas are clinically classified as functional and non-functional tumors, and manifest with a variety of features, including local invasion of surrounding structures and excessive hormone secretion. Functional pituitary adenomas are further classified by the type of hormone they secrete. PITA4 results in excessive production of adrenocorticotropic hormone. This leads to hypersecretion of cortisol by the adrenal glands and ACTH-dependent Cushing syndrome. Clinical manifestations of Cushing syndrome include facial and truncal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes. {ECO:0000269|PubMed:28505279}. Note=The disease is caused by variants affecting the gene represented in this entry.

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

Sequence caution: Sequence=AAH38801.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305}; Sequence=AAH51345.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={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 can remove conjugated ubiquitin from proteins and therefore plays an important regulatory role at the level of protein turnover by preventing degradation. Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains. Catalytic activity is enhanced in the M phase. Involved in cell proliferation. Required to enter into S phase in response to serum stimulation. May regulate T-cell anergy mediated by RNF128 via the formation of a complex containing RNF128 and OTUB1. Probably regulates the stability of STAM2 and RASGRF1. Regulates endosomal ubiquitin dynamics, cargo sorting, membrane traffic at early endosomes, and maintenance of ESCRT-0 stability. The level of protein ubiquitination on endosomes is essential for maintaining the morphology of the organelle. Deubiquitinates EPS15 and controles tyrosine kinase stability. Removes conjugated ubiquitin from EGFR thus regulating EGFR degradation and downstream MAPK signaling. Involved in acrosome biogenesis through interaction with the spermatid ESCRT-0 complex and microtubules. Deubiquitinates BIRC6/bruce and KIF23/MKLP1. Deubiquitinates BACE1 which inhibits BACE1 lysosomal degradation and modulates BACE-mediated APP cleavage and amyloid-beta formation (PubMed:27302062). {ECO:0000269\|PubMed:16520378, ECO:0000269\|PubMed:17711858, ECO:0000269\|PubMed:18329369, ECO:0000269\|PubMed:27302062, ECO:0000269\|PubMed:9628861}.


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:9628861};
Subunit:		Forms a ternary complex with RNF128 and OTUB1. Interacts (via C-terminal UCH catalytic domain) with OTUB1 isoform 1. Interacts with STAM2 (via SH3 domain). Interacts with DNAJB3, EGFR, EPS15, RASGRF1, RNF41, YWHAE, YWHAG and YWHAZ (By similarity). Interacts with NBR1, RASGRF1, RNF41 and IST1. Associates with the ESCRT-0 complex and with microtubules (By similarity). Interacts with BIRC6/bruce and KIF23/MKLP1. {ECO:0000250, ECO:0000269\|PubMed:17035239, ECO:0000269\|PubMed:17711858, ECO:0000269\|PubMed:18329369, ECO:0000269\|PubMed:19129480, ECO:0000269\|PubMed:19427866}.
Subunit:		(Microbial infection) Interacts with Zika virus non-structural protein 1. {ECO:0000269\|PubMed:30065070}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:16520378, ECO:0000269\|PubMed:17711858, ECO:0000269\|PubMed:19427866, ECO:0000269\|PubMed:28505279}. Nucleus {ECO:0000250\|UniProtKB:Q80U87}. Endosome membrane {ECO:0000269\|PubMed:16520378, ECO:0000269\|PubMed:17711858}; Peripheral membrane protein {ECO:0000305}. Cell membrane {ECO:0000269\|PubMed:16520378}; Peripheral membrane protein {ECO:0000305}.
Induction:		Upon growth stimulation in starved human fibroblasts. Decreases in response to growth arrest induced by cell-cell contact. {ECO:0000269\|PubMed:9628861}.
Domain:		The MIT domain is required for endosomal localization, CHMP1B- binding, maintenance of ESCRT-0 stability and EGFR degradation. {ECO:0000269\|PubMed:17711858}.
Domain:		The rhodanese domain is sufficient for RNF41-binding. {ECO:0000250}.
Ptm:		Phosphorylation of Ser-718 is essential for interaction with YWHAE and for cytosol localization. Undergoes dephosphorylation at Ser-718 in the M phase. Tyrosine-phosphorylated in its N-terminal half in an EGFR- dependent manner. {ECO:0000250}.
Ptm:		Ubiquitinated. Inactive form is mostly monoubiquitinated, but polyubiquitination happens too. Ubiquitination is increased in EGF- stimulated cells. Ubiquitination of active form is undetectable, suggesting a possibility that USP8 deubiquitinates itself, thereby regulating its own function (By similarity). {ECO:0000250}.
Disease:		Pituitary adenoma 4, ACTH-secreting (PITA4) [MIM:219090]: A form of pituitary adenoma, a neoplasm of the pituitary gland and one of the most common neuroendocrine tumors. Pituitary adenomas are clinically classified as functional and non-functional tumors, and manifest with a variety of features, including local invasion of surrounding structures and excessive hormone secretion. Functional pituitary adenomas are further classified by the type of hormone they secrete. PITA4 results in excessive production of adrenocorticotropic hormone. This leads to hypersecretion of cortisol by the adrenal glands and ACTH-dependent Cushing syndrome. Clinical manifestations of Cushing syndrome include facial and truncal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes. {ECO:0000269\|PubMed:28505279}. Note=The disease is caused by variants affecting the gene represented in this entry.
Similarity:		Belongs to the peptidase C19 family. {ECO:0000305}.
Sequence caution:		Sequence=AAH38801.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305}; Sequence=AAH51345.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305};