UniProt functional annotation for O88522



	UniProt functional annotation for O88522

UniProt code: O88522.

Organism: Mus musculus (Mouse).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.

Function: Regulatory subunit of the IKK core complex which phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF-kappa-B complex and ultimately the degradation of the inhibitor (PubMed:9927690). Its binding to scaffolding polyubiquitin plays a key role in IKK activation by multiple signaling receptor pathways. Can recognize and bind both 'Lys- 63'-linked and linear polyubiquitin upon cell stimulation, with a much highr affinity for linear polyubiquitin. Could be implicated in NF- kappa-B-mediated protection from cytokine toxicity. Essential for viral activation of IRF3. Involved in TLR3- and IFIH1-mediated antiviral innate response; this function requires 'Lys-27'-linked polyubiquitination (By similarity). {ECO:0000250|UniProtKB:Q9Y6K9, ECO:0000269|PubMed:9927690}.

Subunit: Homodimer; disulfide-linked (By similarity). 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 (PubMed:11080499). The IKK core complex seems to associate with regulatory or adapter proteins to form a IKK- signalosome holo-complex (PubMed:11080499). The IKK complex associates with TERF2IP/RAP1, leading to promote IKK-mediated phosphorylation of RELA/p65 (PubMed:20622870). Part of a complex composed of NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG and CREBBP (By similarity). Interacts with COPS3, CYLD, NALP2, TRPC4AP and PIDD1 (By similarity). Interacts with ATM; the complex is exported from the nucleus (By similarity). Interacts with TRAF6 (By similarity). Interacts with IKBKE (By similarity). Interacts with TANK; the interaction is enhanced by IKBKE and TBK1 (By similarity). Part of a ternary complex consisting of TANK, IKBKB and IKBKG (PubMed:12133833). Interacts with ZFAND5 (By similarity). Interacts with RIPK2 (By similarity). Interacts with TNIP1 and TNFAIP3; TNIP1 facilitates the TNFAIP3-mediated de-ubiquitination of IKBKG (By similarity). Interacts with TNFAIP3; the interaction is induced by TNF stimulation and by polyubiquitin (By similarity). Binds (via UBAN region) polyubiquitin; binds both 'Lys-63'-linked and linear polyubiquitin, with higher affinity for linear ubiquitin (PubMed:19303852, PubMed:19854204). Interacts with NLRP10 (By similarity). Interacts with TANK; this interaction increases in response to DNA damage (By similarity). Interacts with USP10; this interaction increases in response to DNA damage (By similarity). Interacts with ZC3H12A; this interaction increases in response to DNA damage (By similarity). Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation (By similarity). Interacts with TRIM29; this interaction induces IKBKG/NEMO ubiquitination and proteolytic degradation (By similarity). Interacts with TRIM13; this interaction leads to IKBKG/NEMO ubiquitination (By similarity). Interacts with ARFIP2 (By similarity). Interacts with RIPK1 (PubMed:31519886). Interacts with (ubiquitinated) BCL10; interaction with polyubiquitinated BCL10 via both 'Lys-63'-linked and linear ubiquitin is required for TCR-induced NF-kappa-B activation (By similarity). {ECO:0000250|UniProtKB:Q9Y6K9, ECO:0000269|PubMed:11080499, ECO:0000269|PubMed:12133833, ECO:0000269|PubMed:19303852, ECO:0000269|PubMed:19854204, ECO:0000269|PubMed:20622870, ECO:0000269|PubMed:31519886}.

Subcellular location: Cytoplasm {ECO:0000250|UniProtKB:Q9Y6K9}. Nucleus {ECO:0000250|UniProtKB:Q9Y6K9}. Note=Sumoylated NEMO accumulates in the nucleus in response to genotoxic stress. {ECO:0000250|UniProtKB:Q9Y6K9}.

Domain: The leucine-zipper domain and the CCHC NOA-type zinc-fingers constitute the UBAN region and are essential for polyubiquitin binding and for the activation of IRF3. {ECO:0000250|UniProtKB:Q9Y6K9}.

Ptm: Phosphorylation at Ser-68 attenuates aminoterminal homodimerization. {ECO:0000250|UniProtKB:Q9Y6K9}.

Ptm: Polyubiquitinated on Lys-278 through 'Lys-63'; the ubiquitination is mediated by NOD2 and RIPK2 and probably plays a role in signaling by facilitating interactions with ubiquitin domain-containing proteins and activates the NF-kappa-B pathway. Polyubiquitinated on Lys-392 through 'Lys-63'; the ubiquitination is mediated by BCL10, MALT1 and TRAF6 and probably plays a role in signaling by facilitating interactions with ubiquitin domain-containing proteins and activates the NF-kappa-B pathway. Monoubiquitinated on Lys-270 and Lys-302; promotes nuclear export. Polyubiquitinated through 'Lys-27' by TRIM23; involved in antiviral innate and inflammatory responses. Linear polyubiquitinated on Lys-111, Lys-143, Lys-226, Lys-246, Lys-270, Lys-278, Lys-285, Lys- 295, Lys-302 and Lys-319; the head-to-tail polyubiquitination is mediated by the LUBAC complex and plays a key role in NF-kappa-B activation. Deubiquitinated by USP10 in a TANK-dependent and -independent manner, leading to the negative regulation of NF-kappa-B signaling upon DNA damage (By similarity). {ECO:0000250|UniProtKB:Q9Y6K9}.

Ptm: Sumoylated on Lys-270 and Lys-302 with SUMO1; the modification results in phosphorylation of Ser-85 by ATM leading to a replacement of the sumoylation by mono-ubiquitination on these residues. {ECO:0000250|UniProtKB:Q9Y6K9}.

Ptm: Neddylated by TRIM40, resulting in stabilization of NFKBIA and down-regulation of NF-kappa-B activity. {ECO:0000250|UniProtKB:Q9Y6K9}.

Annotations taken from UniProtKB at the EBI.


Organism:		Mus musculus (Mouse).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.



Function:		Regulatory subunit of the IKK core complex which phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF-kappa-B complex and ultimately the degradation of the inhibitor (PubMed:9927690). Its binding to scaffolding polyubiquitin plays a key role in IKK activation by multiple signaling receptor pathways. Can recognize and bind both 'Lys- 63'-linked and linear polyubiquitin upon cell stimulation, with a much highr affinity for linear polyubiquitin. Could be implicated in NF- kappa-B-mediated protection from cytokine toxicity. Essential for viral activation of IRF3. Involved in TLR3- and IFIH1-mediated antiviral innate response; this function requires 'Lys-27'-linked polyubiquitination (By similarity). {ECO:0000250\|UniProtKB:Q9Y6K9, ECO:0000269\|PubMed:9927690}.


Subunit:		Homodimer; disulfide-linked (By similarity). 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 (PubMed:11080499). The IKK core complex seems to associate with regulatory or adapter proteins to form a IKK- signalosome holo-complex (PubMed:11080499). The IKK complex associates with TERF2IP/RAP1, leading to promote IKK-mediated phosphorylation of RELA/p65 (PubMed:20622870). Part of a complex composed of NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG and CREBBP (By similarity). Interacts with COPS3, CYLD, NALP2, TRPC4AP and PIDD1 (By similarity). Interacts with ATM; the complex is exported from the nucleus (By similarity). Interacts with TRAF6 (By similarity). Interacts with IKBKE (By similarity). Interacts with TANK; the interaction is enhanced by IKBKE and TBK1 (By similarity). Part of a ternary complex consisting of TANK, IKBKB and IKBKG (PubMed:12133833). Interacts with ZFAND5 (By similarity). Interacts with RIPK2 (By similarity). Interacts with TNIP1 and TNFAIP3; TNIP1 facilitates the TNFAIP3-mediated de-ubiquitination of IKBKG (By similarity). Interacts with TNFAIP3; the interaction is induced by TNF stimulation and by polyubiquitin (By similarity). Binds (via UBAN region) polyubiquitin; binds both 'Lys-63'-linked and linear polyubiquitin, with higher affinity for linear ubiquitin (PubMed:19303852, PubMed:19854204). Interacts with NLRP10 (By similarity). Interacts with TANK; this interaction increases in response to DNA damage (By similarity). Interacts with USP10; this interaction increases in response to DNA damage (By similarity). Interacts with ZC3H12A; this interaction increases in response to DNA damage (By similarity). Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation (By similarity). Interacts with TRIM29; this interaction induces IKBKG/NEMO ubiquitination and proteolytic degradation (By similarity). Interacts with TRIM13; this interaction leads to IKBKG/NEMO ubiquitination (By similarity). Interacts with ARFIP2 (By similarity). Interacts with RIPK1 (PubMed:31519886). Interacts with (ubiquitinated) BCL10; interaction with polyubiquitinated BCL10 via both 'Lys-63'-linked and linear ubiquitin is required for TCR-induced NF-kappa-B activation (By similarity). {ECO:0000250\|UniProtKB:Q9Y6K9, ECO:0000269\|PubMed:11080499, ECO:0000269\|PubMed:12133833, ECO:0000269\|PubMed:19303852, ECO:0000269\|PubMed:19854204, ECO:0000269\|PubMed:20622870, ECO:0000269\|PubMed:31519886}.
Subcellular location:		Cytoplasm {ECO:0000250\|UniProtKB:Q9Y6K9}. Nucleus {ECO:0000250\|UniProtKB:Q9Y6K9}. Note=Sumoylated NEMO accumulates in the nucleus in response to genotoxic stress. {ECO:0000250\|UniProtKB:Q9Y6K9}.
Domain:		The leucine-zipper domain and the CCHC NOA-type zinc-fingers constitute the UBAN region and are essential for polyubiquitin binding and for the activation of IRF3. {ECO:0000250\|UniProtKB:Q9Y6K9}.
Ptm:		Phosphorylation at Ser-68 attenuates aminoterminal homodimerization. {ECO:0000250\|UniProtKB:Q9Y6K9}.
Ptm:		Polyubiquitinated on Lys-278 through 'Lys-63'; the ubiquitination is mediated by NOD2 and RIPK2 and probably plays a role in signaling by facilitating interactions with ubiquitin domain-containing proteins and activates the NF-kappa-B pathway. Polyubiquitinated on Lys-392 through 'Lys-63'; the ubiquitination is mediated by BCL10, MALT1 and TRAF6 and probably plays a role in signaling by facilitating interactions with ubiquitin domain-containing proteins and activates the NF-kappa-B pathway. Monoubiquitinated on Lys-270 and Lys-302; promotes nuclear export. Polyubiquitinated through 'Lys-27' by TRIM23; involved in antiviral innate and inflammatory responses. Linear polyubiquitinated on Lys-111, Lys-143, Lys-226, Lys-246, Lys-270, Lys-278, Lys-285, Lys- 295, Lys-302 and Lys-319; the head-to-tail polyubiquitination is mediated by the LUBAC complex and plays a key role in NF-kappa-B activation. Deubiquitinated by USP10 in a TANK-dependent and -independent manner, leading to the negative regulation of NF-kappa-B signaling upon DNA damage (By similarity). {ECO:0000250\|UniProtKB:Q9Y6K9}.
Ptm:		Sumoylated on Lys-270 and Lys-302 with SUMO1; the modification results in phosphorylation of Ser-85 by ATM leading to a replacement of the sumoylation by mono-ubiquitination on these residues. {ECO:0000250\|UniProtKB:Q9Y6K9}.
Ptm:		Neddylated by TRIM40, resulting in stabilization of NFKBIA and down-regulation of NF-kappa-B activity. {ECO:0000250\|UniProtKB:Q9Y6K9}.