E3 ubiquitin-protein ligase Itchy homolog; Itch; atrophin-1-interacting protein 4; AIP4; NFE2-associated polypeptide 1; NAPP1 (ITCH)
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Function
- E3 ubiquitin-protein ligase
- catalyzes Lys-29-, Lys-48- & Lys-63-linked ubiquitin conjugation
- involved in the control of inflammatory signaling pathways
- component of a ubiquitin-editing protein complex, comprising also TNFAIP3, TAX1BP1 & RNF11, that ensures the transient nature of inflammatory signaling pathways
- promotes association of the complex after TNF stimulation
- once the complex is formed, TNFAIP3 deubiquitinates Lys-63 polyubiquitin chains on RIPK1 & catalyzes formation of Lys-48-polyubiquitin chains
- this leads to RIPK1 proteosomal degradation & consequently termination of the TNF- or LPS-mediated activation of NFKB1
- ubiquitinates RIPK2 by Lys-63-linked conjugation & influences NOD2-dependent signal transduction pathways
- regulates transcriptional activity of several transcription factors, & probably plays a role in regulation of the immune response
- ubiquitinates NFE2 by Lys-63 linkages & is implicated in control of the development of hematopoietic lineages
- regulator of T helper (TH2) cytokine development through its ability to induce JUNB ubiquitination & degradation (putative)
- ubiquitinates SNX9
- ubiquitinates CXCR4 & HGS/HRS & regulates sorting of CXCR4 to the degradative pathway
- involved in negative regulation of MAVS-dependent cellular antiviral responses
- ubiquitinates MAVS through Lys-48-linked conjugation resulting in MAVS proteosomal degradation
- involved in regulation of apoptosis & reactive oxygen species levels through ubiquitination & proteosomal degradation of TXNIP
- mediates antiapoptotic activity of EGF through ubiquitination & proteosomal degradation of p15 BID
- targets DTX1 for lysosomal degradation & controls NOTCH1 degradation, in the absence of ligand, through Lys-29- linked polyubiquitination
- activated by NDFIP1- & NDFIP2-binding
- protein modification; protein ubiquitination
- on T-cell activation, phosphorylation by the JNK cascade on Ser & Thr surrounding the PRR domain accelerates ubiquitination & degradation of JUN & JUNB
- 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 & the HECT domain &, thus exposing the HECT domain (putative)
- phosphorylation by FYN reduces interaction with JUNB & negatively controls JUN ubiquitination & degradation
- ubiquitinated; autopolyubiquitination with Lys-63 linkages which does not lead to protein degradation
- monomer (putative) interacts (via its WW domains) with DRPLA
- interacts with epstein-Barr virus LMP2A
- interacts (via its WW domains) with OCNL, NOTCH1 & JUN
- interacts (via WW domain 2) with N4BP1; leading to inhibits its E3 ubiquitin-protein ligase activity (putative)
- interacts with JUNB; the interaction promotes ITCH-mediated ubiquitination & degradation of JUNB
- interacts with NDFIP1 & NDFIP2; this interaction activates the E3 ubiquitin-protein ligase & may induce its recruitment to exosomes (putative)
- interacts with ARHGEF7
- interacts with RNF11
- interacts (via the WW 1 domain) with NFE2 (via 1st PXY motif); the interaction promotes Lys-63-linked ubiquitination of NFE2, retains it in the cytoplasm & prevents its transactivation activity
- interacts with FYN; the interaction phosphorylates ITCH on Tyr-420 decreasing binding of JUNB
- interacts (via WW domains) with CXCR4 (via C-terminus); the interaction depends on CXCR4 phosphorylation
- interacts (via WW domains) with PCBP2 within a complex containing ITCH, MAVS & PCBP2
- interacts (via WW domains) with TXNIP (via C-terminus)
- interacts with p15 BID
- interacts with SNX9 & SNX18
- interacts with SPG20
- interacts with DTX1
Structure
- contains 1 C2 domain
- contains 1 HECT domain
- contains 4 WW domains
Compartment
- cell membrane
- cytoplasm (putative)
- nucleus (putative)
- associates with endocytic vesicles
- may be recruited to exosomes by NDFIP1
Alternative splicing
named isoforms=2
Expression
widely expressed
Pathology
- defects in ITCH are the cause of syndromic multisystem autoimmune disease