UniProt functional annotation for Q96EP0



	UniProt functional annotation for Q96EP0

UniProt code: Q96EP0.

Organism: Homo sapiens (Human).

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

Function: E3 ubiquitin-protein ligase component of the LUBAC complex which conjugates linear ('Met-1'-linked) polyubiquitin chains to substrates and plays a key role in NF-kappa-B activation and regulation of inflammation (PubMed:17006537, PubMed:19136968, PubMed:20005846, PubMed:21455173, PubMed:21455180, PubMed:21455181, PubMed:22863777, PubMed:28189684). LUBAC conjugates linear polyubiquitin to IKBKG and RIPK1 and is involved in activation of the canonical NF-kappa-B and the JNK signaling pathways (PubMed:17006537, PubMed:19136968, PubMed:20005846, PubMed:21455173, PubMed:21455180, PubMed:21455181, PubMed:22863777, PubMed:28189684). Linear ubiquitination mediated by the LUBAC complex interferes with TNF-induced cell death and thereby prevents inflammation (PubMed:21455173, PubMed:28189684). LUBAC is recruited to the TNF-R1 signaling complex (TNF-RSC) following polyubiquitination of TNF-RSC components by BIRC2 and/or BIRC3 and to conjugate linear polyubiquitin to IKBKG and possibly other components contributing to the stability of the complex (PubMed:20005846, PubMed:27458237). Together with OTULIN, the LUBAC complex regulates the canonical Wnt signaling during angiogenesis (PubMed:23708998). RNF31 is required for linear ubiquitination of BCL10, thereby promoting TCR- induced NF-kappa-B activation (PubMed:27777308). Binds polyubiquitin of different linkage types (PubMed:23708998). {ECO:0000269|PubMed:17006537, ECO:0000269|PubMed:19136968, ECO:0000269|PubMed:20005846, ECO:0000269|PubMed:21455173, ECO:0000269|PubMed:21455180, ECO:0000269|PubMed:21455181, ECO:0000269|PubMed:22863777, ECO:0000269|PubMed:23708998, ECO:0000269|PubMed:27458237, ECO:0000269|PubMed:27777308, ECO:0000269|PubMed:28189684}.

Catalytic activity: Reaction=[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L- cysteine + [acceptor protein]-N(6)-ubiquitinyl-L-lysine.; EC=2.3.2.31; Evidence={ECO:0000269|PubMed:17006537, ECO:0000269|PubMed:19136968, ECO:0000269|PubMed:20005846};

Subunit: Component of the LUBAC complex (linear ubiquitin chain assembly complex) which consists of SHARPIN, RBCK1 and RNF31 (PubMed:17006537, PubMed:21455173, PubMed:21455180, PubMed:21455181). LUBAC has a MW of approximately 600 kDa suggesting a heteromultimeric assembly of its subunits (PubMed:17006537, PubMed:21455173, PubMed:21455180, PubMed:21455181). Associates with the TNF-R1 signaling complex (TNF-RSC) in a stimulation-dependent manner (PubMed:20005846). Interacts (via the PUB domain) with OTULIN (via the PIM motif); the interaction is direct (PubMed:23708998, PubMed:24726323, PubMed:24726327). Interacts (via the PUB domain) with VCP (via the PIM motif) (PubMed:24726327). Interacts (via the PUB domain) with SPATA2 (via the PIM motif); interaction is direct and bridges RNF31 and CYLD (PubMed:27458237, PubMed:27545878, PubMed:28189684, PubMed:27591049). Interacts with CYLD; the interaction is indirect and is mediated via SPATA2 (PubMed:27458237, PubMed:27545878, PubMed:26997266). Interacts with MUSK (By similarity). Interacts with CARD11, promoting linear ubiquitination of BCL10 (PubMed:27777308). {ECO:0000250|UniProtKB:Q924T7, ECO:0000269|PubMed:17006537, ECO:0000269|PubMed:20005846, ECO:0000269|PubMed:21455173, ECO:0000269|PubMed:21455180, ECO:0000269|PubMed:21455181, ECO:0000269|PubMed:22430200, ECO:0000269|PubMed:23708998, ECO:0000269|PubMed:24726323, ECO:0000269|PubMed:24726327, ECO:0000269|PubMed:26997266, ECO:0000269|PubMed:27458237, ECO:0000269|PubMed:27545878, ECO:0000269|PubMed:27591049, ECO:0000269|PubMed:27777308, ECO:0000269|PubMed:28189684}.

Subcellular location: Cytoplasm {ECO:0000250|UniProtKB:Q924T7}.

Tissue specificity: Expressed in both normal and transformed breast epithelial cell lines. {ECO:0000269|PubMed:15093743}.

Domain: The PUB domain mediates interaction with the PIM motifs of VCP and RNF31, with a strong preference for RNF31. {ECO:0000269|PubMed:24726323, ECO:0000269|PubMed:24726327}.

Domain: The RanBP2-type zinc fingers mediate the specific interaction with ubiquitin. {ECO:0000269|PubMed:21455181}.

Domain: The UBA domain mediates association with RBCK1/HOIL1 via interaction with its UBL domain.

Domain: RING 1 and IBR zinc-fingers catalyze the first step transfer of ubiquitin from the E2 onto RING 2, to transiently form a HECT-like covalent thioester intermediate. {ECO:0000269|PubMed:22863777}.

Domain: The linear ubiquitin chain determining domain (LDD) mediates the final transfer of ubiquitin from RING 2 onto the N-terminus of a target ubiquitin. {ECO:0000269|PubMed:22863777}.

Ptm: Autoubiquitinated (PubMed:24726323). Interaction with OTULIN is required to suppress formation of 'Met-1'-linked polyubiquitin chains and prevent subsequent inactivation of the LUBAC complex (PubMed:24726323). {ECO:0000269|PubMed:24726323}.

Ptm: Cleaved by caspase during apoptosis. {ECO:0000269|PubMed:28189684}.

Similarity: Belongs to the RBR family. {ECO:0000305}.

Sequence caution: Sequence=BAB15675.1; Type=Erroneous termination; Note=Truncated C-terminus.; Evidence={ECO:0000305}; Sequence=BAB15675.1; Type=Frameshift; Evidence={ECO:0000305}; Sequence=BAB15675.1; Type=Miscellaneous discrepancy; Note=Intron retention.; Evidence={ECO:0000305}; Sequence=BAB70948.1; Type=Erroneous initiation; 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:		E3 ubiquitin-protein ligase component of the LUBAC complex which conjugates linear ('Met-1'-linked) polyubiquitin chains to substrates and plays a key role in NF-kappa-B activation and regulation of inflammation (PubMed:17006537, PubMed:19136968, PubMed:20005846, PubMed:21455173, PubMed:21455180, PubMed:21455181, PubMed:22863777, PubMed:28189684). LUBAC conjugates linear polyubiquitin to IKBKG and RIPK1 and is involved in activation of the canonical NF-kappa-B and the JNK signaling pathways (PubMed:17006537, PubMed:19136968, PubMed:20005846, PubMed:21455173, PubMed:21455180, PubMed:21455181, PubMed:22863777, PubMed:28189684). Linear ubiquitination mediated by the LUBAC complex interferes with TNF-induced cell death and thereby prevents inflammation (PubMed:21455173, PubMed:28189684). LUBAC is recruited to the TNF-R1 signaling complex (TNF-RSC) following polyubiquitination of TNF-RSC components by BIRC2 and/or BIRC3 and to conjugate linear polyubiquitin to IKBKG and possibly other components contributing to the stability of the complex (PubMed:20005846, PubMed:27458237). Together with OTULIN, the LUBAC complex regulates the canonical Wnt signaling during angiogenesis (PubMed:23708998). RNF31 is required for linear ubiquitination of BCL10, thereby promoting TCR- induced NF-kappa-B activation (PubMed:27777308). Binds polyubiquitin of different linkage types (PubMed:23708998). {ECO:0000269\|PubMed:17006537, ECO:0000269\|PubMed:19136968, ECO:0000269\|PubMed:20005846, ECO:0000269\|PubMed:21455173, ECO:0000269\|PubMed:21455180, ECO:0000269\|PubMed:21455181, ECO:0000269\|PubMed:22863777, ECO:0000269\|PubMed:23708998, ECO:0000269\|PubMed:27458237, ECO:0000269\|PubMed:27777308, ECO:0000269\|PubMed:28189684}.


Catalytic activity:		Reaction=[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L- cysteine + [acceptor protein]-N(6)-ubiquitinyl-L-lysine.; EC=2.3.2.31; Evidence={ECO:0000269\|PubMed:17006537, ECO:0000269\|PubMed:19136968, ECO:0000269\|PubMed:20005846};
Subunit:		Component of the LUBAC complex (linear ubiquitin chain assembly complex) which consists of SHARPIN, RBCK1 and RNF31 (PubMed:17006537, PubMed:21455173, PubMed:21455180, PubMed:21455181). LUBAC has a MW of approximately 600 kDa suggesting a heteromultimeric assembly of its subunits (PubMed:17006537, PubMed:21455173, PubMed:21455180, PubMed:21455181). Associates with the TNF-R1 signaling complex (TNF-RSC) in a stimulation-dependent manner (PubMed:20005846). Interacts (via the PUB domain) with OTULIN (via the PIM motif); the interaction is direct (PubMed:23708998, PubMed:24726323, PubMed:24726327). Interacts (via the PUB domain) with VCP (via the PIM motif) (PubMed:24726327). Interacts (via the PUB domain) with SPATA2 (via the PIM motif); interaction is direct and bridges RNF31 and CYLD (PubMed:27458237, PubMed:27545878, PubMed:28189684, PubMed:27591049). Interacts with CYLD; the interaction is indirect and is mediated via SPATA2 (PubMed:27458237, PubMed:27545878, PubMed:26997266). Interacts with MUSK (By similarity). Interacts with CARD11, promoting linear ubiquitination of BCL10 (PubMed:27777308). {ECO:0000250\|UniProtKB:Q924T7, ECO:0000269\|PubMed:17006537, ECO:0000269\|PubMed:20005846, ECO:0000269\|PubMed:21455173, ECO:0000269\|PubMed:21455180, ECO:0000269\|PubMed:21455181, ECO:0000269\|PubMed:22430200, ECO:0000269\|PubMed:23708998, ECO:0000269\|PubMed:24726323, ECO:0000269\|PubMed:24726327, ECO:0000269\|PubMed:26997266, ECO:0000269\|PubMed:27458237, ECO:0000269\|PubMed:27545878, ECO:0000269\|PubMed:27591049, ECO:0000269\|PubMed:27777308, ECO:0000269\|PubMed:28189684}.
Subcellular location:		Cytoplasm {ECO:0000250\|UniProtKB:Q924T7}.
Tissue specificity:		Expressed in both normal and transformed breast epithelial cell lines. {ECO:0000269\|PubMed:15093743}.
Domain:		The PUB domain mediates interaction with the PIM motifs of VCP and RNF31, with a strong preference for RNF31. {ECO:0000269\|PubMed:24726323, ECO:0000269\|PubMed:24726327}.
Domain:		The RanBP2-type zinc fingers mediate the specific interaction with ubiquitin. {ECO:0000269\|PubMed:21455181}.
Domain:		The UBA domain mediates association with RBCK1/HOIL1 via interaction with its UBL domain.
Domain:		RING 1 and IBR zinc-fingers catalyze the first step transfer of ubiquitin from the E2 onto RING 2, to transiently form a HECT-like covalent thioester intermediate. {ECO:0000269\|PubMed:22863777}.
Domain:		The linear ubiquitin chain determining domain (LDD) mediates the final transfer of ubiquitin from RING 2 onto the N-terminus of a target ubiquitin. {ECO:0000269\|PubMed:22863777}.
Ptm:		Autoubiquitinated (PubMed:24726323). Interaction with OTULIN is required to suppress formation of 'Met-1'-linked polyubiquitin chains and prevent subsequent inactivation of the LUBAC complex (PubMed:24726323). {ECO:0000269\|PubMed:24726323}.
Ptm:		Cleaved by caspase during apoptosis. {ECO:0000269\|PubMed:28189684}.
Similarity:		Belongs to the RBR family. {ECO:0000305}.
Sequence caution:		Sequence=BAB15675.1; Type=Erroneous termination; Note=Truncated C-terminus.; Evidence={ECO:0000305}; Sequence=BAB15675.1; Type=Frameshift; Evidence={ECO:0000305}; Sequence=BAB15675.1; Type=Miscellaneous discrepancy; Note=Intron retention.; Evidence={ECO:0000305}; Sequence=BAB70948.1; Type=Erroneous initiation; Evidence={ECO:0000305};