UniProt functional annotation for O14920



	UniProt functional annotation for O14920

UniProt code: O14920.

Organism: Homo sapiens (Human).

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

Function: Serine kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses (PubMed:30337470). Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation. Phosphorylates inhibitors of NF-kappa-B on 2 critical serine residues. These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome. In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. In addition to the NF-kappa-B inhibitors, phosphorylates several other components of the signaling pathway including NEMO/IKBKG, NF-kappa-B subunits RELA and NFKB1, as well as IKK-related kinases TBK1 and IKBKE (PubMed:11297557, PubMed:20410276). IKK-related kinase phosphorylations may prevent the overproduction of inflammatory mediators since they exert a negative regulation on canonical IKKs. Phosphorylates FOXO3, mediating the TNF- dependent inactivation of this pro-apoptotic transcription factor (PubMed:15084260). Also phosphorylates other substrates including NCOA3, BCL10 and IRS1 (PubMed:17213322). Within the nucleus, acts as an adapter protein for NFKBIA degradation in UV-induced NF-kappa-B activation (PubMed:11297557). Phosphorylates RIPK1 at 'Ser-25' which represses its kinase activity and consequently prevents TNF-mediated RIPK1-dependent cell death (By similarity). Phosphorylates the C- terminus of IRF5, stimulating IRF5 homodimerization and translocation into the nucleus (PubMed:25326418). {ECO:0000250|UniProtKB:O88351, ECO:0000269|PubMed:11297557, ECO:0000269|PubMed:15084260, ECO:0000269|PubMed:17213322, ECO:0000269|PubMed:19716809, ECO:0000269|PubMed:20410276, ECO:0000269|PubMed:20434986, ECO:0000269|PubMed:20797629, ECO:0000269|PubMed:21138416, ECO:0000269|PubMed:25326418, ECO:0000269|PubMed:30337470}.

Catalytic activity: Reaction=ATP + L-seryl-[I-kappa-B protein] = ADP + H(+) + O-phospho-L- seryl-[I-kappa-B protein]; Xref=Rhea:RHEA:19073, Rhea:RHEA- COMP:13698, Rhea:RHEA-COMP:13699, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.10;

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:25326418};

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:0000305};

Subunit: Component of the I-kappa-B-kinase (IKK) core complex consisting of CHUK, IKBKB and IKBKG; probably four alpha/CHUK- beta/IKBKB dimers are associated with four gamma/IKBKG subunits. The IKK core complex seems to associate with regulatory or adapter proteins to form a IKK-signalosome holo-complex (PubMed:12612076). The IKK complex associates with TERF2IP/RAP1, leading to promote IKK-mediated phosphorylation of RELA/p65 (By similarity). Part of a complex composed of NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG and CREBBP (PubMed:11971985). Part of a 70-90 kDa complex at least consisting of CHUK/IKKA, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14 (PubMed:9751059). Found in a membrane raft complex, at least composed of BCL10, CARD11, DPP4 and IKBKB (PubMed:17287217). Interacts with SQSTM1 through PRKCZ or PRKCI (PubMed:10356400). Forms an NGF-induced complex with IKBKB, PRKCI and TRAF6 (By similarity). May interact with MAVS/IPS1 (PubMed:16177806). Interacts with NALP2 (PubMed:15456791). Interacts with TICAM1 (PubMed:14739303). Interacts with FAF1; the interaction disrupts the IKK complex formation (PubMed:17684021). Interacts with ATM (PubMed:16497931). Part of a ternary complex consisting of TANK, IKBKB and IKBKG (PubMed:12133833). Interacts with NIBP; the interaction is direct (PubMed:15951441). Interacts with ARRB1 and ARRB2 (PubMed:15173580). Interacts with TRIM21 (PubMed:19675099). Interacts with NLRC5; prevents IKBKB phosphorylation and kinase activity (PubMed:20434986). Interacts with PDPK1 (PubMed:16207722). Interacts with EIF2AK2/PKR (PubMed:10848580). The phosphorylated form interacts with PPM1A and PPM1B (PubMed:18930133). Interacts with ZNF268 isoform 2; the interaction is further increased in a TNF-alpha-dependent manner (PubMed:23091055). Interacts with IKBKE (PubMed:23453969). Interacts with NAA10, leading to NAA10 degradation (PubMed:19716809). Interacts with FOXO3 (PubMed:15084260). Interacts with AKAP13 (PubMed:23090968). Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation (PubMed:26334375). Interacts with LRRC14; disrupts IKBKB-IKBKG interaction preventing I-kappa-B- kinase (IKK) core complex formation and leading to a decrease of IKBKB phosphorylation and NF-kappaB activation (PubMed:27426725). Interacts with SASH1 (PubMed:23776175). Interacts with ARFIP2 (PubMed:26296658). {ECO:0000250|UniProtKB:O88351, ECO:0000250|UniProtKB:Q9QY78, ECO:0000269|PubMed:10356400, ECO:0000269|PubMed:10848580, ECO:0000269|PubMed:11971985, ECO:0000269|PubMed:12133833, ECO:0000269|PubMed:12612076, ECO:0000269|PubMed:14739303, ECO:0000269|PubMed:15084260, ECO:0000269|PubMed:15173580, ECO:0000269|PubMed:15456791, ECO:0000269|PubMed:15951441, ECO:0000269|PubMed:16177806, ECO:0000269|PubMed:16207722, ECO:0000269|PubMed:16497931, ECO:0000269|PubMed:17287217, ECO:0000269|PubMed:17684021, ECO:0000269|PubMed:18930133, ECO:0000269|PubMed:19675099, ECO:0000269|PubMed:19716809, ECO:0000269|PubMed:20434986, ECO:0000269|PubMed:23091055, ECO:0000269|PubMed:23453969, ECO:0000269|PubMed:23776175, ECO:0000269|PubMed:26296658, ECO:0000269|PubMed:26334375, ECO:0000269|PubMed:27426725, ECO:0000269|PubMed:9751059}.

Subunit: (Microbial infection) Interacts with Yersinia YopJ. {ECO:0000269|PubMed:16728640}.

Subunit: (Microbial infection) Interacts with vaccinia virus protein B14. {ECO:0000269|PubMed:29748387}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:20797629}. Nucleus {ECO:0000269|PubMed:20797629}. Membrane raft {ECO:0000269|PubMed:17287217}. Note=Colocalized with DPP4 in membrane rafts. {ECO:0000269|PubMed:17287217}.

Tissue specificity: Highly expressed in heart, placenta, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis and peripheral blood.

Domain: The kinase domain is located in the N-terminal region. The leucine zipper is important to allow homo- and hetero-dimerization. At the C-terminal region is located the region responsible for the interaction with NEMO/IKBKG. {ECO:0000269|PubMed:18626576}.

Ptm: Upon cytokine stimulation, phosphorylated on Ser-177 and Ser-181 by MEKK1 and/or MAP3K14/NIK as well as TBK1 and PRKCZ; which enhances activity. Once activated, autophosphorylates on the C-terminal serine cluster; which decreases activity and prevents prolonged activation of the inflammatory response. Phosphorylated by the IKK-related kinases TBK1 and IKBKE, which is associated with reduced CHUK/IKKA and IKBKB activity and NF-kappa-B-dependent gene transcription. Dephosphorylated at Ser-177 and Ser-181 by PPM1A and PPM1B. {ECO:0000269|PubMed:10022904, ECO:0000269|PubMed:10195894, ECO:0000269|PubMed:10783893, ECO:0000269|PubMed:16207722}.

Ptm: (Microbial infection) Acetylation of Thr-180 by Yersinia YopJ prevents phosphorylation and activation, thus blocking the I-kappa-B pathway. {ECO:0000269|PubMed:16728640, ECO:0000269|PubMed:17116858}.

Ptm: Ubiquitinated. Monoubiquitination involves TRIM21 that leads to inhibition of Tax-induced NF-kappa-B signaling. According to PubMed:19675099, 'Ser-163' does not serve as a monoubiquitination site. According to PubMed:16267042, ubiquitination on 'Ser-163' modulates phosphorylation on C-terminal serine residues. {ECO:0000269|PubMed:16267042, ECO:0000269|PubMed:19675099}.

Ptm: (Microbial infection) Monoubiquitination by TRIM21 is disrupted by Yersinia YopJ. {ECO:0000269|PubMed:19675099}.

Ptm: Hydroxylated by PHD1/EGLN2, loss of hydroxylation under hypoxic conditions results in activation of NF-kappa-B. {ECO:0000269|PubMed:17114296}.

Disease: Immunodeficiency 15B (IMD15B) [MIM:615592]: An autosomal recessive primary immunodeficiency disorder characterized by onset in infancy of life-threatening bacterial, fungal, and viral infections and failure to thrive. Laboratory studies show hypo- or agammaglobulinemia with relatively normal numbers of B and T-cells, and impaired differentiation and activation of immune cells. {ECO:0000269|PubMed:24369075}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Immunodeficiency 15A (IMD15A) [MIM:618204]: An autosomal dominant primary immunodeficiency disorder characterized by lymphopenia, inflammation and immune activation of both CD4+ and CD8+ T cells. Patients suffer from recurrent respiratory tract infections, oral candidiasis, and otitis media. {ECO:0000269|PubMed:30337470}. Note=The disease is caused by variants affecting the gene represented in this entry.

Similarity: Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily. {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 kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses (PubMed:30337470). Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation. Phosphorylates inhibitors of NF-kappa-B on 2 critical serine residues. These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome. In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. In addition to the NF-kappa-B inhibitors, phosphorylates several other components of the signaling pathway including NEMO/IKBKG, NF-kappa-B subunits RELA and NFKB1, as well as IKK-related kinases TBK1 and IKBKE (PubMed:11297557, PubMed:20410276). IKK-related kinase phosphorylations may prevent the overproduction of inflammatory mediators since they exert a negative regulation on canonical IKKs. Phosphorylates FOXO3, mediating the TNF- dependent inactivation of this pro-apoptotic transcription factor (PubMed:15084260). Also phosphorylates other substrates including NCOA3, BCL10 and IRS1 (PubMed:17213322). Within the nucleus, acts as an adapter protein for NFKBIA degradation in UV-induced NF-kappa-B activation (PubMed:11297557). Phosphorylates RIPK1 at 'Ser-25' which represses its kinase activity and consequently prevents TNF-mediated RIPK1-dependent cell death (By similarity). Phosphorylates the C- terminus of IRF5, stimulating IRF5 homodimerization and translocation into the nucleus (PubMed:25326418). {ECO:0000250\|UniProtKB:O88351, ECO:0000269\|PubMed:11297557, ECO:0000269\|PubMed:15084260, ECO:0000269\|PubMed:17213322, ECO:0000269\|PubMed:19716809, ECO:0000269\|PubMed:20410276, ECO:0000269\|PubMed:20434986, ECO:0000269\|PubMed:20797629, ECO:0000269\|PubMed:21138416, ECO:0000269\|PubMed:25326418, ECO:0000269\|PubMed:30337470}.


Catalytic activity:		Reaction=ATP + L-seryl-[I-kappa-B protein] = ADP + H(+) + O-phospho-L- seryl-[I-kappa-B protein]; Xref=Rhea:RHEA:19073, Rhea:RHEA- COMP:13698, Rhea:RHEA-COMP:13699, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.10;
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:25326418};
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:0000305};
Subunit:		Component of the I-kappa-B-kinase (IKK) core complex consisting of CHUK, IKBKB and IKBKG; probably four alpha/CHUK- beta/IKBKB dimers are associated with four gamma/IKBKG subunits. The IKK core complex seems to associate with regulatory or adapter proteins to form a IKK-signalosome holo-complex (PubMed:12612076). The IKK complex associates with TERF2IP/RAP1, leading to promote IKK-mediated phosphorylation of RELA/p65 (By similarity). Part of a complex composed of NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG and CREBBP (PubMed:11971985). Part of a 70-90 kDa complex at least consisting of CHUK/IKKA, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14 (PubMed:9751059). Found in a membrane raft complex, at least composed of BCL10, CARD11, DPP4 and IKBKB (PubMed:17287217). Interacts with SQSTM1 through PRKCZ or PRKCI (PubMed:10356400). Forms an NGF-induced complex with IKBKB, PRKCI and TRAF6 (By similarity). May interact with MAVS/IPS1 (PubMed:16177806). Interacts with NALP2 (PubMed:15456791). Interacts with TICAM1 (PubMed:14739303). Interacts with FAF1; the interaction disrupts the IKK complex formation (PubMed:17684021). Interacts with ATM (PubMed:16497931). Part of a ternary complex consisting of TANK, IKBKB and IKBKG (PubMed:12133833). Interacts with NIBP; the interaction is direct (PubMed:15951441). Interacts with ARRB1 and ARRB2 (PubMed:15173580). Interacts with TRIM21 (PubMed:19675099). Interacts with NLRC5; prevents IKBKB phosphorylation and kinase activity (PubMed:20434986). Interacts with PDPK1 (PubMed:16207722). Interacts with EIF2AK2/PKR (PubMed:10848580). The phosphorylated form interacts with PPM1A and PPM1B (PubMed:18930133). Interacts with ZNF268 isoform 2; the interaction is further increased in a TNF-alpha-dependent manner (PubMed:23091055). Interacts with IKBKE (PubMed:23453969). Interacts with NAA10, leading to NAA10 degradation (PubMed:19716809). Interacts with FOXO3 (PubMed:15084260). Interacts with AKAP13 (PubMed:23090968). Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation (PubMed:26334375). Interacts with LRRC14; disrupts IKBKB-IKBKG interaction preventing I-kappa-B- kinase (IKK) core complex formation and leading to a decrease of IKBKB phosphorylation and NF-kappaB activation (PubMed:27426725). Interacts with SASH1 (PubMed:23776175). Interacts with ARFIP2 (PubMed:26296658). {ECO:0000250\|UniProtKB:O88351, ECO:0000250\|UniProtKB:Q9QY78, ECO:0000269\|PubMed:10356400, ECO:0000269\|PubMed:10848580, ECO:0000269\|PubMed:11971985, ECO:0000269\|PubMed:12133833, ECO:0000269\|PubMed:12612076, ECO:0000269\|PubMed:14739303, ECO:0000269\|PubMed:15084260, ECO:0000269\|PubMed:15173580, ECO:0000269\|PubMed:15456791, ECO:0000269\|PubMed:15951441, ECO:0000269\|PubMed:16177806, ECO:0000269\|PubMed:16207722, ECO:0000269\|PubMed:16497931, ECO:0000269\|PubMed:17287217, ECO:0000269\|PubMed:17684021, ECO:0000269\|PubMed:18930133, ECO:0000269\|PubMed:19675099, ECO:0000269\|PubMed:19716809, ECO:0000269\|PubMed:20434986, ECO:0000269\|PubMed:23091055, ECO:0000269\|PubMed:23453969, ECO:0000269\|PubMed:23776175, ECO:0000269\|PubMed:26296658, ECO:0000269\|PubMed:26334375, ECO:0000269\|PubMed:27426725, ECO:0000269\|PubMed:9751059}.
Subunit:		(Microbial infection) Interacts with Yersinia YopJ. {ECO:0000269\|PubMed:16728640}.
Subunit:		(Microbial infection) Interacts with vaccinia virus protein B14. {ECO:0000269\|PubMed:29748387}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:20797629}. Nucleus {ECO:0000269\|PubMed:20797629}. Membrane raft {ECO:0000269\|PubMed:17287217}. Note=Colocalized with DPP4 in membrane rafts. {ECO:0000269\|PubMed:17287217}.
Tissue specificity:		Highly expressed in heart, placenta, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis and peripheral blood.
Domain:		The kinase domain is located in the N-terminal region. The leucine zipper is important to allow homo- and hetero-dimerization. At the C-terminal region is located the region responsible for the interaction with NEMO/IKBKG. {ECO:0000269\|PubMed:18626576}.
Ptm:		Upon cytokine stimulation, phosphorylated on Ser-177 and Ser-181 by MEKK1 and/or MAP3K14/NIK as well as TBK1 and PRKCZ; which enhances activity. Once activated, autophosphorylates on the C-terminal serine cluster; which decreases activity and prevents prolonged activation of the inflammatory response. Phosphorylated by the IKK-related kinases TBK1 and IKBKE, which is associated with reduced CHUK/IKKA and IKBKB activity and NF-kappa-B-dependent gene transcription. Dephosphorylated at Ser-177 and Ser-181 by PPM1A and PPM1B. {ECO:0000269\|PubMed:10022904, ECO:0000269\|PubMed:10195894, ECO:0000269\|PubMed:10783893, ECO:0000269\|PubMed:16207722}.
Ptm:		(Microbial infection) Acetylation of Thr-180 by Yersinia YopJ prevents phosphorylation and activation, thus blocking the I-kappa-B pathway. {ECO:0000269\|PubMed:16728640, ECO:0000269\|PubMed:17116858}.
Ptm:		Ubiquitinated. Monoubiquitination involves TRIM21 that leads to inhibition of Tax-induced NF-kappa-B signaling. According to PubMed:19675099, 'Ser-163' does not serve as a monoubiquitination site. According to PubMed:16267042, ubiquitination on 'Ser-163' modulates phosphorylation on C-terminal serine residues. {ECO:0000269\|PubMed:16267042, ECO:0000269\|PubMed:19675099}.
Ptm:		(Microbial infection) Monoubiquitination by TRIM21 is disrupted by Yersinia YopJ. {ECO:0000269\|PubMed:19675099}.
Ptm:		Hydroxylated by PHD1/EGLN2, loss of hydroxylation under hypoxic conditions results in activation of NF-kappa-B. {ECO:0000269\|PubMed:17114296}.
Disease:		Immunodeficiency 15B (IMD15B) [MIM:615592]: An autosomal recessive primary immunodeficiency disorder characterized by onset in infancy of life-threatening bacterial, fungal, and viral infections and failure to thrive. Laboratory studies show hypo- or agammaglobulinemia with relatively normal numbers of B and T-cells, and impaired differentiation and activation of immune cells. {ECO:0000269\|PubMed:24369075}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Immunodeficiency 15A (IMD15A) [MIM:618204]: An autosomal dominant primary immunodeficiency disorder characterized by lymphopenia, inflammation and immune activation of both CD4+ and CD8+ T cells. Patients suffer from recurrent respiratory tract infections, oral candidiasis, and otitis media. {ECO:0000269\|PubMed:30337470}. Note=The disease is caused by variants affecting the gene represented in this entry.
Similarity:		Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily. {ECO:0000255\|PROSITE- ProRule:PRU00159}.