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.

ITCH

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:14602072, PubMed:17028573, PubMed:16387660, PubMed:18718448, PubMed:18718449, PubMed:11046148, PubMed:19592251, PubMed:19116316, PubMed:19881509, PubMed:20491914, PubMed:20392206, PubMed:20068034, PubMed:23146885, PubMed:24790097, PubMed:25631046).
Catalyzes 'Lys-29'-, 'Lys-48'- and 'Lys-63'-linked ubiquitin conjugation (PubMed:17028573, PubMed:18718448, PubMed:19131965, PubMed: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, PubMed: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, PubMed:23146885).
Targets DTX1 for lysosomal degradation and controls NOTCH1 degradation, in the absence of ligand, through 'Lys-29'-linked polyubiquitination (PubMed:17028573, PubMed:18628966, PubMed:23886940).
Ubiquitinates SNX9 (PubMed:20491914).
Ubiquitinates MAP3K7 through 'Lys-48'-linked conjugation (By similarity).
Involved in the regulation of apoptosis and reactive oxygen species levels through the ubiquitination and proteasomal degradation of TXNIP (PubMed:20068034).
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).

Apoptotic processIEA:UniProtKB-KW
Defense response to virusIEA:UniProtKB-KW
Inflammatory response1 PublicationNAS:UniProtKB
Innate immune responseIEA:UniProtKB-KW
Negative regulation of alpha-beta T cell proliferationIEA:Ensembl
Negative regulation of apoptotic processManual Assertion Based On ExperimentIMP:UniProtKB
Negative regulation of defense response to virusManual Assertion Based On ExperimentIMP:UniProtKB
Negative regulation of JNK cascadeISS:BHF-UCL
Negative regulation of NF-kappaB transcription factor activityISS:BHF-UCL
Negative regulation of type I interferon productionTAS:Reactome
Nucleotide-binding oligomerization domain containing signaling pathwayTAS:Reactome
Positive regulation of protein catabolic processManual Assertion Based On ExperimentIBA:GO_Central
Positive regulation of receptor catabolic processManual Assertion Based On ExperimentIMP:UniProtKB
Positive regulation of T cell anergyIEA:Ensembl
Proteasome-mediated ubiquitin-dependent protein catabolic processManual Assertion Based On ExperimentIMP:ARUK-UCL
Protein autoubiquitinationManual Assertion Based On ExperimentIMP:UniProtKB
Protein K29-linked ubiquitinationManual Assertion Based On ExperimentIDA:UniProtKB
Protein K48-linked ubiquitinationManual Assertion Based On ExperimentIDA:UniProtKB
Protein K63-linked ubiquitinationManual Assertion Based On ExperimentIDA:UniProtKB
Protein polyubiquitinationManual Assertion Based On ExperimentIBA:GO_Central
Protein ubiquitinationManual Assertion Based On ExperimentIDA:UniProtKB
Regulation of cell growth1 PublicationNAS:UniProtKB
Regulation of hematopoietic stem cell differentiationTAS:Reactome
Regulation of protein deubiquitinationISS:BHF-UCL
Ubiquitin-dependent protein catabolic processManual Assertion Based On ExperimentIDA:MGI
Viral entry into host cellManual Assertion Based On ExperimentTAS:UniProtKB

Cell membrane; Cytoplasm; Nucleus; Early endosome membrane; Endosome membrane. 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).

Autoimmune disease, multisystem, with facial dysmorphism (ADMFD):
A disorder characterized by organomegaly, failure to thrive, developmental delay, dysmorphic features and autoimmune inflammatory cell infiltration of the lungs, liver and gut.

On T-cell activation, phosphorylation by the JNK cascade on serine and threonine residues surrounding the PRR domain accelerates the ubiquitination and degradation of JUN and JUNB. The increased ITCH catalytic activity due to phosphorylation by JNK1 may occur due to a conformational change disrupting the interaction between the PRR/WW motifs domain and the HECT domain and, thus exposing the HECT domain (By similarity).
Phosphorylation by FYN reduces interaction with JUNB and negatively controls JUN ubiquitination and degradation.
Monoubiquitinated (PubMed:19116316).
Autopolyubiquitinated with 'Lys-63' linkages which does not lead to protein degradation (PubMed:18718449, PubMed:23146885, PubMed:24790097).