ITCH Q96J02

E3泛素蛋白连接酶Itchy同源物 (Itch) (EC 2.3.2.26) (Atrophin-1相互作用蛋白4) (AIP4) (HECT型E3泛素转移酶Itchy同源物) (NFE2相关多肽1) (NAPP1)

功能描述

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, PubMed:14602072, PubMed:15051726, PubMed:16387660, PubMed:17028573, PubMed:18718448, PubMed:18718449, PubMed:19116316, PubMed:19592251, PubMed:19881509, PubMed:20068034, PubMed:20392206, PubMed:20491914, 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, PubMed:34927784). 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). 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, PubMed: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). {ECO:0000250|UniProtKB:Q8C863, ECO:0000269|PubMed:14602072, ECO:0000269|PubMed:15051726, ECO:0000269|PubMed:16387660, ECO:0000269|PubMed:17028573, ECO:0000269|PubMed:18628966, ECO:0000269|PubMed:18718448, ECO:0000269|PubMed:18718449, ECO:0000269|PubMed:19116316, ECO:0000269|PubMed:19131965, ECO:0000269|PubMed:19592251, ECO:0000269|PubMed:19881509, ECO:0000269|PubMed:20068034, ECO:0000269|PubMed:20392206, ECO:0000269|PubMed:20491914, ECO:0000269|PubMed:23146885, ECO:0000269|PubMed:23886940, ECO:0000269|PubMed:24790097, ECO:0000269|PubMed:25631046, ECO:0000269|PubMed:29378950, ECO:0000269|PubMed:30328013}. FUNCTION: 作为一种E3泛素-蛋白连接酶，以硫酯的形式接受来自E2泛素结合酶的泛素，然后直接将泛素转移到靶向底物 (PubMed:11046148, PubMed:14602072, PubMed:15051726, PubMed:16387660, PubMed:17028573, PubMed:18718448, PubMed:18718449, PubMed:19116316, PubMed:19592251, PubMed:19881509, PubMed:20068034, PubMed:20392206, PubMed:20491914, PubMed:23146885, PubMed:24790097, PubMed:25631046)。催化'Lys-29'-、'Lys-48'-和'Lys-63'-连接的泛素结合 (PubMed:17028573, PubMed:18718448, PubMed:19131965, PubMed:19881509)。参与炎症信号通路的控制 (PubMed:19131965)。是一个泛素编辑蛋白复合物的必需组分，该复合物还包括TNFAIP3、TAX1BP1和RNF11，确保炎症信号通路的瞬时性 (PubMed:19131965)。在TNF刺激后促进复合物的结合 (PubMed:19131965)。一旦复合物形成，TNFAIP3对RIPK1上的'Lys-63'多聚泛素链进行去泛素化，并催化'Lys-48'-多聚泛素链的形成 (PubMed:19131965)。这导致RIPK1蛋白酶体降解，从而终止TNF或LPS介导的NFKB1活化 (PubMed:19131965)。通过'Lys-63'-连接的结合对RIPK2进行泛素化，并影响NOD2依赖的信号转导通路 (PubMed:19592251)。调节几种转录因子的转录活性，并可能在免疫反应的调节中起重要作用 (PubMed:18718448, PubMed:20491914)。通过'Lys-63'连接对NFE2进行泛素化，并参与造血谱系发育的控制 (PubMed:18718448)。介导JUN泛素化和降解 (By similarity)。介导JUNB泛素化和降解 (PubMed:16387660)。通过诱导JUNB泛素化和降解，成为2型辅助T (Th2)细胞因子产生的关键调节因子 (By similarity)。参与MAVS依赖性细胞抗病毒反应的负调节 (PubMed:19881509)。通过'Lys-48'-连接的结合对MAVS进行泛素化，导致MAVS蛋白酶体降解 (PubMed:19881509)。配体刺激后，可能通过调节PI42KA活性，调节Wnt受体FZD4向降解性内吞途径的分选

组织特异性

Widely expressed.

亚细胞定位

Cell membrane