ITCH

This gene encodes a member of the Nedd4 family of HECT domain E3 ubiquitin ligases. HECT domain E3 ubiquitin ligases transfer ubiquitin from E2 ubiquitin-conjugating enzymes to protein substrates, thus targeting specific proteins for lysosomal degradation. The encoded protein plays a role in multiple cellular processes including erythroid and lymphoid cell differentiation and the regulation of immune responses. Mutations in this gene are a cause of syndromic multisystem autoimmune disease. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]
Diseases associated with ITCH include Autoimmune Disease, Multisystem, With Facial Dysmorphism and Syndromic Multisystem Autoimmune Disease Due To Itch Deficiency. Among its related pathways are Gene expression (Transcription) and Infectious disease. Gene Ontology (GO) annotations related to this gene include ligase activity and ubiquitin protein ligase activity. An important paralog of this gene is WWP1.
Acts as an Acts as an E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates (PubMed:11046148, 14602072, 15051726, 16387660, 17028573, 18718448, 18718449, 19116316, 19592251, 19881509, 20068034, 20392206, 20491914, 23146885, 24790097, 25631046).
Catalyzes 'Lys-29'-, 'Lys-48'- and 'Lys-63'-linked ubiquitin conjugation (PubMed:17028573, 18718448, 19131965, 19881509).
Involved in the control of inflammatory signaling pathways (PubMed:19131965).
Essential component of a ubiquitin-editing protein complex, comprising also TNFAIP3, TAX1BP1 and RNF11, that ensures the transient nature of inflammatory signaling pathways (PubMed:19131965).
Promotes the association of the complex after TNF stimulation (PubMed:19131965).
Once the complex is formed, TNFAIP3 deubiquitinates 'Lys-63' polyubiquitin chains on RIPK1 and catalyzes the formation of 'Lys-48'-polyubiquitin chains (PubMed:19131965).
This leads to RIPK1 proteasomal degradation and consequently termination of the TNF- or LPS-mediated activation of NFKB1 (PubMed:19131965).
Ubiquitinates RIPK2 by 'Lys-63'-linked conjugation and influences NOD2-dependent signal transduction pathways (PubMed:19592251).
Regulates the transcriptional activity of several transcription factors, and probably plays an important role in the regulation of immune response (PubMed:18718448, 20491914).
Ubiquitinates NFE2 by 'Lys-63' linkages and is implicated in the control of the development of hematopoietic lineages (PubMed:18718448).
Mediates JUN ubiquitination and degradation (By similarity).
Mediates JUNB ubiquitination and degradation (PubMed:16387660).
Critical regulator of type 2 helper T (Th2) cell cytokine production by inducing JUNB ubiquitination and degradation (By similarity).
Involved in the negative regulation of MAVS-dependent cellular antiviral responses (PubMed:19881509).
Ubiquitinates MAVS through 'Lys-48'-linked conjugation resulting in MAVS proteasomal degradation (PubMed:19881509).
Following ligand stimulation, regulates sorting of Wnt receptor FZD4 to the degradative endocytic pathway probably by modulating PI42KA activity (PubMed:23146885).
Ubiquitinates PI4K2A and negatively regulates its catalytic activity (PubMed:23146885).
Ubiquitinates chemokine receptor CXCR4 and regulates sorting of CXCR4 to the degradative endocytic pathway following ligand stimulation by ubiquitinating endosomal sorting complex required for transport ESCRT-0 components HGS and STAM (PubMed:14602072, 23146885, 34927784).
Targets DTX1 for lysosomal degradation and controls NOTCH1 degradation, in the absence of ligand, through 'Lys-29'-linked polyubiquitination (PubMed:17028573, 18628966, 23886940).
Ubiquitinates SNX9 (PubMed:20491914).
Ubiquitinates MAP3K7 through 'Lys-48'-linked conjugation (By similarity).
Together with UBR5, involved in the regulation of apoptosis and reactive oxygen species levels through the ubiquitination and proteasomal degradation of TXNIP: catalyzes 'Lys-48'-/'Lys-63'-branched ubiquitination of TXNIP (PubMed:20068034, 29378950).
ITCH synthesizes 'Lys-63'-linked chains, while UBR5 is branching multiple 'Lys-48'-linked chains of substrate initially modified (PubMed:29378950).
Mediates the antiapoptotic activity of epidermal growth factor through the ubiquitination and proteasomal degradation of p15 BID (PubMed:20392206).
Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1 (PubMed:25631046).
Inhibits the replication of influenza A virus (IAV) via ubiquitination of IAV matrix protein 1 (M1) through 'Lys-48'-linked conjugation resulting in M1 proteasomal degradation (PubMed:30328013).
Ubiquitinates NEDD9/HEF1, resulting in proteasomal degradation of NEDD9/HEF1 (PubMed:15051726).
Activated by NDFIP1- and NDFIP2-binding (PubMed:25631046).
Activated by PI4K2A-binding (PubMed:23146885).
Inhibited by DTX3L-binding (PubMed:24790097).
Inhibited by N4BP1 binding (By similarity).
Cell membrane; Peripheral membrane protein; Cytoplasmic side {ECO:0000269 PubMed:14602072 | ECO:0000305 PubMed:14602072}
Cytoplasm {ECO:0000269 PubMed:14602072}
Nucleus {ECO:0000269 PubMed:20858735}
Early endosome membrane; Peripheral membrane protein; Cytoplasmic side {ECO:0000269 PubMed:14602072, 23146885, 24790097 | ECO:0000305 PubMed:14602072, 23146885, 24790097}
Endosome membrane; Peripheral membrane protein; Cytoplasmic side {ECO:0000269 PubMed:23146885 | ECO:0000305 PubMed:23146885}
Note: May be recruited to exosomes by NDFIP1 (PubMed:18819914). Localizes to plasma membrane upon CXCL12 stimulation where it co-localizes with CXCL4 (PubMed:14602072). Localization to early endosomes is increased upon CXCL12 stimulation where it co-localizes with DTX3L and CXCL4 (PubMed:24790097) {ECO:0000269 PubMed:14602072, 18819914, 24790097}
Quaternary structure:
Monomer.
Part of a ternary complex composed of SMAD3, ITCH/AIP4 and NEDD9/HEF1; within the complex NEDD9/HEF1 interacts (via N-terminus) with ITCH/AIP4 (via WW domains); the complex mediates ubiquitination and proteasomal degradation of NEDD9/HEF1 (PubMed:15051726).
Interacts (via WW domains) with OCNL (By similarity).
Interacts (via WW domains) with NOTCH1 (By similarity).
Interacts (via WW domains) with JUN (By similarity).
Interacts with JUNB; the interaction promotes ITCH-mediated ubiquitination and degradation of JUNB (PubMed:16387660).
Interacts with FYN; the interaction phosphorylates ITCH on Tyr-420 decreasing binding of JUNB (PubMed:16387660).
Interacts (via WW domain 2) with N4BP1; the interaction inhibits the E3 ubiquitin-protein ligase activity (By similarity).
Interacts with NDFIP1 and NDFIP2; this interaction activates the E3 ubiquitin-protein ligase and may induce its recruitment to exosomes (By similarity).
Interacts with ARHGEF7 (PubMed:17652093).
Interacts with RNF11 (PubMed:14559117, 19131965).
Interacts (via the WW 1 domain) with NFE2 (via the PXY motif 1); the interaction promotes 'Lys-63'-linked ubiquitination of NFE2, retains it in the cytoplasm and prevents its transactivation activity (PubMed:11318614, 18718448).
Interacts (via WW domains) with CXCR4 (via C-terminus); the interaction depends on CXCR4 phosphorylation (PubMed:19116316).
Found in a complex with E3 ligase DTX3L and ESCRT-0 components HGS and STAM (PubMed:24790097).
Interacts with DTX3L (via C-terminus); the interaction is increased upon CXCL12 stimulation and inhibits ITCH catalytic activity (the interaction is direct) (PubMed:24790097).
Interacts with HGS (PubMed:14602072).
Interacts (via WW domains) with PCBP2 within a complex containing ITCH, MAVS and PCBP2 (PubMed:19881509).
Interacts (via WW domains) with TXNIP (via C-terminus) (PubMed:20068034).
Interacts with p15 BID (PubMed:20392206).
Interacts with ERBB4 (PubMed:20858735).
Interacts with DTX1 (PubMed:17028573).
Interacts with SPART (PubMed:19580544).
Interacts with SNX9 and SNX18 (PubMed:20491914).
Interacts (via its WW domains) with ATN1 (PubMed:9647693).
Interacts (via WW domains) with SGK3 (PubMed:16888620).
Interacts with CBLC (PubMed:12226085).
Interacts with OTUD7B (PubMed:22179831).
Interacts (via WW domain 1,2 and 3) with PI4K2A; the interaction inhibits PI4K2A catalytic activity and promotes ITCH catalytic activity (PubMed:23146885).
Interacts with ARRDC4 (PubMed:23236378).
Part of a complex containing ITCH, NDFIP1 and MAP3K7 (By similarity).
Interacts with UBE2L3; the interaction is mediated by NDFIP1 (PubMed:25632008).
Interacts with MAPK8/JNK1 (By similarity).
Interacts (via WW domains) with ARRDC1 (via PPxY motifs); the interaction is direct and participates in the recruitment of the ubiquitin-protein ligase ITCH to the NOTCH1 receptor (PubMed:21191027, 23886940).
Interacts (via WW domains) with ARRDC2 (PubMed:21191027).
Interacts (via WW domains) with ARRDC3 (PubMed:21191027, 23886940).
Interacts directly with LDLRAD3; this interaction promotes ITCH auto-ubiquitination leading to its degradation (PubMed:26854353).
Interacts with ENTREP1; enhances the ubiquitination of CXCR4 by ITCH and its subsequent endocytosis (PubMed:34927784).