UniProt functional annotation for Q13114



	UniProt functional annotation for Q13114

UniProt code: Q13114.

Organism: Homo sapiens (Human).

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

Function: Regulates pathways leading to the activation of NF-kappa-B and MAP kinases, and plays a central role in the regulation of B-cell survival. Part of signaling pathways leading to the production of cytokines and interferon. Required for normal antibody isotype switching from IgM to IgG. Plays a role T-cell dependent immune responses. Plays a role in the regulation of antiviral responses. Is an essential constituent of several E3 ubiquitin-protein ligase complexes. May have E3 ubiquitin-protein ligase activity and promote 'Lys-63'- linked ubiquitination of target proteins. Inhibits activation of NF- kappa-B in response to LTBR stimulation. Inhibits TRAF2-mediated activation of NF-kappa-B. Down-regulates proteolytic processing of NFKB2, and thereby inhibits non-canonical activation of NF-kappa-B. Promotes ubiquitination and proteasomal degradation of MAP3K14. {ECO:0000269|PubMed:15084608, ECO:0000269|PubMed:15383523, ECO:0000269|PubMed:17991829, ECO:0000269|PubMed:19937093, ECO:0000269|PubMed:20097753, ECO:0000269|PubMed:20185819, ECO:0000269|PubMed:32562145}.

Catalytic activity: Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L- cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.; EC=2.3.2.27;

Subunit: Homotrimer. Heterotrimer with TRAF2 and TRAF5. Interacts with LTBR/TNFRSF3, TNFRSF4, TNFRSF5/CD40, TNFRSF8/CD30, TNFRSF13C TNFRSF17/BCMA, TLR4 and EDAR. Interacts with MAP3K5, MAP3K14, TRAIP/TRIP, TDP2/TTRAP, TANK/ITRAF and TRAF3IP1. Interaction with TNFRSF5/CD40 is modulated by TANK/ITRAF, which competes for the same binding site. Interacts with TICAM1. Interacts with TRAFD1. Interacts with OTUB1, OTUB2 and OTUD5. Interacts with RNF216, OPTN and TBK1. Identified in a complex with TRAF2, MAP3K14 and BIRC3. Interacts with BIRC2 and BIRC3. Upon exposure to bacterial lipopolysaccharide (LPS), recruited to a transient complex containing TLR4, TRAF3, TRAF6, IKBKG, MAP3K7, MYD88, TICAM1, BIRC2, BIRC3 and UBE2N (By similarity). Interacts with Epstein-Barr virus protein LMP1. Interacts (via RING- type zinc finger domain) with SRC. Interacts with CARD14. Interacts (via MATH domain) with PTPN22; the interaction promotes TRAF3 polyubiquitination (PubMed:23871208). Interacts with MAVS (PubMed:19893624, PubMed:27980081). Directly interacts with DDX3X; this interaction stimulates TRAF3 'Lys-63' ubiquitination (PubMed:27980081). Interacts with IRF3 (PubMed:27980081). Interacts with IKBKE in the course of Sendai virus infection (PubMed:27980081). Interacts with TRIM35 (PubMed:32562145). Interacts with GAPDH; promoting TRAF3 ubiquitination (PubMed:27387501). {ECO:0000250|UniProtKB:Q60803, ECO:0000269|PubMed:10037686, ECO:0000269|PubMed:10523862, ECO:0000269|PubMed:10764746, ECO:0000269|PubMed:10791955, ECO:0000269|PubMed:10809768, ECO:0000269|PubMed:10903733, ECO:0000269|PubMed:10984535, ECO:0000269|PubMed:11035039, ECO:0000269|PubMed:12005438, ECO:0000269|PubMed:14517219, ECO:0000269|PubMed:15084608, ECO:0000269|PubMed:15383523, ECO:0000269|PubMed:15585864, ECO:0000269|PubMed:16009714, ECO:0000269|PubMed:17991829, ECO:0000269|PubMed:19419966, ECO:0000269|PubMed:19893624, ECO:0000269|PubMed:19996094, ECO:0000269|PubMed:20097753, ECO:0000269|PubMed:20174559, ECO:0000269|PubMed:21302310, ECO:0000269|PubMed:23871208, ECO:0000269|PubMed:27387501, ECO:0000269|PubMed:27980081, ECO:0000269|PubMed:32562145, ECO:0000269|PubMed:7527023, ECO:0000269|PubMed:7530216, ECO:0000269|PubMed:7533327, ECO:0000269|PubMed:7859281, ECO:0000269|PubMed:8663299, ECO:0000269|PubMed:8710854, ECO:0000269|PubMed:9162022, ECO:0000269|PubMed:9168896, ECO:0000269|PubMed:9275204, ECO:0000269|PubMed:9418902, ECO:0000269|PubMed:9488716, ECO:0000269|PubMed:9718306, ECO:0000269|PubMed:9774460, ECO:0000269|PubMed:9774977}.

Subcellular location: Cytoplasm {ECO:0000305}. Endosome {ECO:0000250|UniProtKB:Q60803}. Mitochondrion. Note=Undergoes endocytosis together with TLR4 upon LPS signaling (By similarity). Associated with mitochondria in response to virus. {ECO:0000250|UniProtKB:Q60803}.

Domain: The MATH/TRAF domain binds to receptor cytoplasmic domains.

Domain: The Ring-type zinc finger domain is required for its function in down-regulation of NFKB2 proteolytic processing. {ECO:0000250|UniProtKB:Q60803}.

Ptm: Undergoes 'Lys-48'-linked polyubiquitination, leading to its proteasomal degradation in response to signaling by TNFSF13B, TLR4 or through CD40. 'Lys-48'-linked polyubiquitinated form is deubiquitinated by OTUD7B, preventing TRAF3 proteolysis and over-activation of non- canonical NF-kappa-B. Undergoes 'Lys-63'-linked ubiquitination during early stages of virus infection, and 'Lys-48'-linked ubiquitination during later stages. Undergoes both 'Lys-48'-linked and 'Lys-63'-linked ubiquitination in response to TLR3 and TLR4 signaling. 'Lys-63'-linked ubiquitination can be mediated by TRIM35. Deubiquitinated by OTUB1, OTUB2 and OTUD5. Undergoes 'Lys-63'-linked deubiquitination by MYSM1 to terminate the pattern-recognition receptors/PRRs pathways (By similarity). {ECO:0000250|UniProtKB:Q60803, ECO:0000269|PubMed:17991829, ECO:0000269|PubMed:19893624, ECO:0000269|PubMed:19937093, ECO:0000269|PubMed:19996094, ECO:0000269|PubMed:20097753, ECO:0000269|PubMed:27980081, ECO:0000269|PubMed:32562145}.

Disease: Encephalopathy, acute, infection-induced, Herpes-specific, 5 (IIAE5) [MIM:614849]: A rare complication of human herpesvirus 1 (HHV- 1) infection, occurring in only a small minority of HHV-1 infected individuals. It is characterized by hemorrhagic necrosis of parts of the temporal and frontal lobes. Onset is over several days and involves fever, headache, seizures, stupor, and often coma, frequently with a fatal outcome. {ECO:0000269|PubMed:20832341}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.

Similarity: Belongs to the TNF receptor-associated factor family. A subfamily. {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:		Regulates pathways leading to the activation of NF-kappa-B and MAP kinases, and plays a central role in the regulation of B-cell survival. Part of signaling pathways leading to the production of cytokines and interferon. Required for normal antibody isotype switching from IgM to IgG. Plays a role T-cell dependent immune responses. Plays a role in the regulation of antiviral responses. Is an essential constituent of several E3 ubiquitin-protein ligase complexes. May have E3 ubiquitin-protein ligase activity and promote 'Lys-63'- linked ubiquitination of target proteins. Inhibits activation of NF- kappa-B in response to LTBR stimulation. Inhibits TRAF2-mediated activation of NF-kappa-B. Down-regulates proteolytic processing of NFKB2, and thereby inhibits non-canonical activation of NF-kappa-B. Promotes ubiquitination and proteasomal degradation of MAP3K14. {ECO:0000269\|PubMed:15084608, ECO:0000269\|PubMed:15383523, ECO:0000269\|PubMed:17991829, ECO:0000269\|PubMed:19937093, ECO:0000269\|PubMed:20097753, ECO:0000269\|PubMed:20185819, ECO:0000269\|PubMed:32562145}.


Catalytic activity:		Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L- cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.; EC=2.3.2.27;
Subunit:		Homotrimer. Heterotrimer with TRAF2 and TRAF5. Interacts with LTBR/TNFRSF3, TNFRSF4, TNFRSF5/CD40, TNFRSF8/CD30, TNFRSF13C TNFRSF17/BCMA, TLR4 and EDAR. Interacts with MAP3K5, MAP3K14, TRAIP/TRIP, TDP2/TTRAP, TANK/ITRAF and TRAF3IP1. Interaction with TNFRSF5/CD40 is modulated by TANK/ITRAF, which competes for the same binding site. Interacts with TICAM1. Interacts with TRAFD1. Interacts with OTUB1, OTUB2 and OTUD5. Interacts with RNF216, OPTN and TBK1. Identified in a complex with TRAF2, MAP3K14 and BIRC3. Interacts with BIRC2 and BIRC3. Upon exposure to bacterial lipopolysaccharide (LPS), recruited to a transient complex containing TLR4, TRAF3, TRAF6, IKBKG, MAP3K7, MYD88, TICAM1, BIRC2, BIRC3 and UBE2N (By similarity). Interacts with Epstein-Barr virus protein LMP1. Interacts (via RING- type zinc finger domain) with SRC. Interacts with CARD14. Interacts (via MATH domain) with PTPN22; the interaction promotes TRAF3 polyubiquitination (PubMed:23871208). Interacts with MAVS (PubMed:19893624, PubMed:27980081). Directly interacts with DDX3X; this interaction stimulates TRAF3 'Lys-63' ubiquitination (PubMed:27980081). Interacts with IRF3 (PubMed:27980081). Interacts with IKBKE in the course of Sendai virus infection (PubMed:27980081). Interacts with TRIM35 (PubMed:32562145). Interacts with GAPDH; promoting TRAF3 ubiquitination (PubMed:27387501). {ECO:0000250\|UniProtKB:Q60803, ECO:0000269\|PubMed:10037686, ECO:0000269\|PubMed:10523862, ECO:0000269\|PubMed:10764746, ECO:0000269\|PubMed:10791955, ECO:0000269\|PubMed:10809768, ECO:0000269\|PubMed:10903733, ECO:0000269\|PubMed:10984535, ECO:0000269\|PubMed:11035039, ECO:0000269\|PubMed:12005438, ECO:0000269\|PubMed:14517219, ECO:0000269\|PubMed:15084608, ECO:0000269\|PubMed:15383523, ECO:0000269\|PubMed:15585864, ECO:0000269\|PubMed:16009714, ECO:0000269\|PubMed:17991829, ECO:0000269\|PubMed:19419966, ECO:0000269\|PubMed:19893624, ECO:0000269\|PubMed:19996094, ECO:0000269\|PubMed:20097753, ECO:0000269\|PubMed:20174559, ECO:0000269\|PubMed:21302310, ECO:0000269\|PubMed:23871208, ECO:0000269\|PubMed:27387501, ECO:0000269\|PubMed:27980081, ECO:0000269\|PubMed:32562145, ECO:0000269\|PubMed:7527023, ECO:0000269\|PubMed:7530216, ECO:0000269\|PubMed:7533327, ECO:0000269\|PubMed:7859281, ECO:0000269\|PubMed:8663299, ECO:0000269\|PubMed:8710854, ECO:0000269\|PubMed:9162022, ECO:0000269\|PubMed:9168896, ECO:0000269\|PubMed:9275204, ECO:0000269\|PubMed:9418902, ECO:0000269\|PubMed:9488716, ECO:0000269\|PubMed:9718306, ECO:0000269\|PubMed:9774460, ECO:0000269\|PubMed:9774977}.
Subcellular location:		Cytoplasm {ECO:0000305}. Endosome {ECO:0000250\|UniProtKB:Q60803}. Mitochondrion. Note=Undergoes endocytosis together with TLR4 upon LPS signaling (By similarity). Associated with mitochondria in response to virus. {ECO:0000250\|UniProtKB:Q60803}.
Domain:		The MATH/TRAF domain binds to receptor cytoplasmic domains.
Domain:		The Ring-type zinc finger domain is required for its function in down-regulation of NFKB2 proteolytic processing. {ECO:0000250\|UniProtKB:Q60803}.
Ptm:		Undergoes 'Lys-48'-linked polyubiquitination, leading to its proteasomal degradation in response to signaling by TNFSF13B, TLR4 or through CD40. 'Lys-48'-linked polyubiquitinated form is deubiquitinated by OTUD7B, preventing TRAF3 proteolysis and over-activation of non- canonical NF-kappa-B. Undergoes 'Lys-63'-linked ubiquitination during early stages of virus infection, and 'Lys-48'-linked ubiquitination during later stages. Undergoes both 'Lys-48'-linked and 'Lys-63'-linked ubiquitination in response to TLR3 and TLR4 signaling. 'Lys-63'-linked ubiquitination can be mediated by TRIM35. Deubiquitinated by OTUB1, OTUB2 and OTUD5. Undergoes 'Lys-63'-linked deubiquitination by MYSM1 to terminate the pattern-recognition receptors/PRRs pathways (By similarity). {ECO:0000250\|UniProtKB:Q60803, ECO:0000269\|PubMed:17991829, ECO:0000269\|PubMed:19893624, ECO:0000269\|PubMed:19937093, ECO:0000269\|PubMed:19996094, ECO:0000269\|PubMed:20097753, ECO:0000269\|PubMed:27980081, ECO:0000269\|PubMed:32562145}.
Disease:		Encephalopathy, acute, infection-induced, Herpes-specific, 5 (IIAE5) [MIM:614849]: A rare complication of human herpesvirus 1 (HHV- 1) infection, occurring in only a small minority of HHV-1 infected individuals. It is characterized by hemorrhagic necrosis of parts of the temporal and frontal lobes. Onset is over several days and involves fever, headache, seizures, stupor, and often coma, frequently with a fatal outcome. {ECO:0000269\|PubMed:20832341}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.
Similarity:		Belongs to the TNF receptor-associated factor family. A subfamily. {ECO:0000305}.