UniProt functional annotation for O75460



	UniProt functional annotation for O75460

UniProt code: O75460.

Organism: Homo sapiens (Human).

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

Function: Serine/threonine-protein kinase and endoribonuclease that acts as a key sensor for the endoplasmic reticulum unfolded protein response (UPR) (PubMed:11779464, PubMed:11175748, PubMed:12637535, PubMed:9637683, PubMed:21317875, PubMed:28128204). In unstressed cells, the endoplasmic reticulum luminal domain is maintained in its inactive monomeric state by binding to the endoplasmic reticulum chaperone HSPA5/BiP (PubMed:21317875). Accumulation of misfolded proteins in the endoplasmic reticulum causes release of HSPA5/BiP, allowing the luminal domain to homodimerize, promoting autophosphorylation of the kinase domain and subsequent activation of the endoribonuclease activity (PubMed:21317875). The endoribonuclease activity is specific for XBP1 mRNA and excises 26 nucleotides from XBP1 mRNA (PubMed:11779464, PubMed:24508390, PubMed:21317875). The resulting spliced transcript of XBP1 encodes a transcriptional activator protein that up-regulates expression of UPR target genes (PubMed:11779464, PubMed:24508390, PubMed:21317875). Acts as an upstream signal for ER stress-induced GORASP2-mediated unconventional (ER/Golgi-independent) trafficking of CFTR to cell membrane by modulating the expression and localization of SEC16A (PubMed:21884936, PubMed:28067262). {ECO:0000269|PubMed:11175748, ECO:0000269|PubMed:11779464, ECO:0000269|PubMed:12637535, ECO:0000269|PubMed:21317875, ECO:0000269|PubMed:21884936, ECO:0000269|PubMed:28067262, ECO:0000269|PubMed:28128204, ECO:0000269|PubMed:9637683, ECO:0000305|PubMed:24508390}.

Catalytic activity: Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000269|PubMed:21317875, ECO:0000269|PubMed:9637683};

Catalytic activity: Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000269|PubMed:21317875, ECO:0000269|PubMed:9637683};

Cofactor: Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269|PubMed:21317875, ECO:0000269|PubMed:9637683};

Activity regulation: The kinase domain is activated by trans- autophosphorylation following homodimerization (PubMed:12637535, PubMed:9637683). Kinase activity is required for activation of the endoribonuclease domain (PubMed:12637535, PubMed:9637683). Endoribonuclease activity is specifically inhibited by hydroxy-aryl- aldehydes (HAA) (By similarity). {ECO:0000250|UniProtKB:Q9EQY0, ECO:0000269|PubMed:12637535, ECO:0000269|PubMed:9637683}.

Subunit: Monomer (PubMed:29198525, PubMed:16973740). Homodimer; disulfide-linked; homodimerization takes place in response to endoplasmic reticulum stress and promotes activation of the kinase and endoribonuclease activities (PubMed:12637535, PubMed:24508390, PubMed:16973740, PubMed:21317875). Dimer formation is driven by hydrophobic interactions within the N-terminal luminal domains and stabilized by disulfide bridges (PubMed:12637535). Interacts (via the luminal region) with DNAJB9/ERdj4; interaction takes place in unstressed cells and promotes recruitment of HSPA5/BiP (PubMed:29198525). Interacts (via the luminal region) with HSPA5/BiP; HSPA5/BiP is a negative regulator of the unfolded protein response (UPR) that prevents homodimerization of ERN1/IRE1 and subsequent activation of the protein (PubMed:12637535, PubMed:29198525). Interacts with PDIA6, a negative regulator of the UPR; the interaction is direct and disrupts homodimerization (PubMed:24508390). Interacts with DAB2IP (via PH domain); the interaction occurs in a endoplasmic reticulum stress-induced dependent manner and is required for subsequent recruitment of TRAF2 to ERN1/IRE1 (By similarity). Interacts with TAOK3 and TRAF2 (PubMed:11278723). Interacts with RNF13 (PubMed:23378536). Interacts with LACC1 (PubMed:31875558). Interacts (when unphosphorylated) with DDRGK1; interaction is dependent on UFM1 and takes place in response to endoplasmic reticulum stress, regulating ERN1/IRE1-alpha stability (PubMed:28128204). {ECO:0000250|UniProtKB:Q9EQY0, ECO:0000269|PubMed:11278723, ECO:0000269|PubMed:12637535, ECO:0000269|PubMed:16973740, ECO:0000269|PubMed:23378536, ECO:0000269|PubMed:24508390, ECO:0000269|PubMed:28128204, ECO:0000269|PubMed:29198525, ECO:0000269|PubMed:31875558}.

Subcellular location: Endoplasmic reticulum membrane {ECO:0000269|PubMed:9637683}; Single-pass type I membrane protein {ECO:0000269|PubMed:9637683}.

Tissue specificity: Ubiquitously expressed. High levels observed in pancreatic tissue. {ECO:0000269|PubMed:9637683}.

Ptm: Autophosphorylated following homodimerization. Autophosphorylation promotes activation of the endoribonuclease domain. {ECO:0000269|PubMed:12637535, ECO:0000269|PubMed:21317875, ECO:0000269|PubMed:28128204, ECO:0000269|PubMed:9637683}.

Ptm: ADP-ribosylated by PARP16 upon ER stress, which increases both kinase and endonuclease activities. {ECO:0000269|PubMed:23103912}.

Similarity: Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. {ECO:0000255|PROSITE-ProRule:PRU00159}.

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:		Serine/threonine-protein kinase and endoribonuclease that acts as a key sensor for the endoplasmic reticulum unfolded protein response (UPR) (PubMed:11779464, PubMed:11175748, PubMed:12637535, PubMed:9637683, PubMed:21317875, PubMed:28128204). In unstressed cells, the endoplasmic reticulum luminal domain is maintained in its inactive monomeric state by binding to the endoplasmic reticulum chaperone HSPA5/BiP (PubMed:21317875). Accumulation of misfolded proteins in the endoplasmic reticulum causes release of HSPA5/BiP, allowing the luminal domain to homodimerize, promoting autophosphorylation of the kinase domain and subsequent activation of the endoribonuclease activity (PubMed:21317875). The endoribonuclease activity is specific for XBP1 mRNA and excises 26 nucleotides from XBP1 mRNA (PubMed:11779464, PubMed:24508390, PubMed:21317875). The resulting spliced transcript of XBP1 encodes a transcriptional activator protein that up-regulates expression of UPR target genes (PubMed:11779464, PubMed:24508390, PubMed:21317875). Acts as an upstream signal for ER stress-induced GORASP2-mediated unconventional (ER/Golgi-independent) trafficking of CFTR to cell membrane by modulating the expression and localization of SEC16A (PubMed:21884936, PubMed:28067262). {ECO:0000269\|PubMed:11175748, ECO:0000269\|PubMed:11779464, ECO:0000269\|PubMed:12637535, ECO:0000269\|PubMed:21317875, ECO:0000269\|PubMed:21884936, ECO:0000269\|PubMed:28067262, ECO:0000269\|PubMed:28128204, ECO:0000269\|PubMed:9637683, ECO:0000305\|PubMed:24508390}.


Catalytic activity:		Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000269\|PubMed:21317875, ECO:0000269\|PubMed:9637683};
Catalytic activity:		Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000269\|PubMed:21317875, ECO:0000269\|PubMed:9637683};
Cofactor:		Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269\|PubMed:21317875, ECO:0000269\|PubMed:9637683};
Activity regulation:		The kinase domain is activated by trans- autophosphorylation following homodimerization (PubMed:12637535, PubMed:9637683). Kinase activity is required for activation of the endoribonuclease domain (PubMed:12637535, PubMed:9637683). Endoribonuclease activity is specifically inhibited by hydroxy-aryl- aldehydes (HAA) (By similarity). {ECO:0000250\|UniProtKB:Q9EQY0, ECO:0000269\|PubMed:12637535, ECO:0000269\|PubMed:9637683}.
Subunit:		Monomer (PubMed:29198525, PubMed:16973740). Homodimer; disulfide-linked; homodimerization takes place in response to endoplasmic reticulum stress and promotes activation of the kinase and endoribonuclease activities (PubMed:12637535, PubMed:24508390, PubMed:16973740, PubMed:21317875). Dimer formation is driven by hydrophobic interactions within the N-terminal luminal domains and stabilized by disulfide bridges (PubMed:12637535). Interacts (via the luminal region) with DNAJB9/ERdj4; interaction takes place in unstressed cells and promotes recruitment of HSPA5/BiP (PubMed:29198525). Interacts (via the luminal region) with HSPA5/BiP; HSPA5/BiP is a negative regulator of the unfolded protein response (UPR) that prevents homodimerization of ERN1/IRE1 and subsequent activation of the protein (PubMed:12637535, PubMed:29198525). Interacts with PDIA6, a negative regulator of the UPR; the interaction is direct and disrupts homodimerization (PubMed:24508390). Interacts with DAB2IP (via PH domain); the interaction occurs in a endoplasmic reticulum stress-induced dependent manner and is required for subsequent recruitment of TRAF2 to ERN1/IRE1 (By similarity). Interacts with TAOK3 and TRAF2 (PubMed:11278723). Interacts with RNF13 (PubMed:23378536). Interacts with LACC1 (PubMed:31875558). Interacts (when unphosphorylated) with DDRGK1; interaction is dependent on UFM1 and takes place in response to endoplasmic reticulum stress, regulating ERN1/IRE1-alpha stability (PubMed:28128204). {ECO:0000250\|UniProtKB:Q9EQY0, ECO:0000269\|PubMed:11278723, ECO:0000269\|PubMed:12637535, ECO:0000269\|PubMed:16973740, ECO:0000269\|PubMed:23378536, ECO:0000269\|PubMed:24508390, ECO:0000269\|PubMed:28128204, ECO:0000269\|PubMed:29198525, ECO:0000269\|PubMed:31875558}.
Subcellular location:		Endoplasmic reticulum membrane {ECO:0000269\|PubMed:9637683}; Single-pass type I membrane protein {ECO:0000269\|PubMed:9637683}.
Tissue specificity:		Ubiquitously expressed. High levels observed in pancreatic tissue. {ECO:0000269\|PubMed:9637683}.
Ptm:		Autophosphorylated following homodimerization. Autophosphorylation promotes activation of the endoribonuclease domain. {ECO:0000269\|PubMed:12637535, ECO:0000269\|PubMed:21317875, ECO:0000269\|PubMed:28128204, ECO:0000269\|PubMed:9637683}.
Ptm:		ADP-ribosylated by PARP16 upon ER stress, which increases both kinase and endonuclease activities. {ECO:0000269\|PubMed:23103912}.
Similarity:		Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. {ECO:0000255\|PROSITE-ProRule:PRU00159}.