E3 ubiquitin-protein ligase Itchy homolog

Definition:

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. Catalyzes 'Lys-29'-, 'Lys-48'- and 'Lys-63'-linked ubiquitin conjugation. Involved in the control of inflammatory signaling pathways. Essential component of a ubiquitin-editing protein complex, comprising also TNFAIP3, TAX1BP1 and RNF11, that ensures the transient nature of inflammatory signaling pathways. Promotes the association of the complex after TNF stimulation. Once the complex is formed, TNFAIP3 deubiquitinates 'Lys-63' polyubiquitin chains on RIPK1 and catalyzes the formation of 'Lys-48'-polyubiquitin chains. This leads to RIPK1 proteasomal degradation and consequently termination of the TNF- or LPS-mediated activation of NFKB1. Ubiquitinates RIPK2 by 'Lys-63'-linked conjugation and influences NOD2-dependent signal transduction pathways. Regulates the transcriptional activity of several transcription factors, and probably plays an important role in the regulation of immune response. Ubiquitinates NFE2 by 'Lys-63' linkages and is implicated in the control of the development of hematopoietic lineages. Mediates JUN ubiquitination and degradation (By similarity). Mediates JUNB ubiquitination and degradation. 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. Ubiquitinates MAVS through 'Lys-48'-linked conjugation resulting in MAVS proteasomal degradation. Following ligand stimulation, regulates sorting of Wnt receptor FZD4 to the degradative endocytic pathway probably by modulating PI42KA activity. Ubiquitinates PI4K2A and negatively regulates its catalytic activity. 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. Targets DTX1 for lysosomal degradation and controls NOTCH1 degradation, in the absence of ligand, through 'Lys-29'-linked polyubiquitination. Ubiquitinates SNX9. 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. Mediates the antiapoptotic activity of epidermal growth factor through the ubiquitination and proteasomal degradation of p15 BID. Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1. 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. Ubiquitinates NEDD9/HEF1, resulting in proteosomal degradation of NEDD9/HEF1.

References:

[1]. Madina Mahesutihan, et al. CypA Regulates AIP4-Mediated M1 Ubiquitination of Influenza A Virus. Virol Sin. 2018 Oct;33(5):440-448. [Content Brief]

[2]. Flavia Scialpi, et al. Itch self-polyubiquitylation occurs through lysine-63 linkages. Biochem Pharmacol. 2008 Dec 1;76(11):1515-21. [Content Brief]

[3]. Patricia Chastagner, et al. AIP4/Itch regulates Notch receptor degradation in the absence of ligand. PLoS One. 2008 Jul 16;3(7):e2735. [Content Brief]

[4]. Fuping You, et al. PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin ligase AIP4. Nat Immunol. 2009 Dec;10(12):1300-8. [Content Brief]

[5]. Noula Shembade, et al. The ubiquitin-editing enzyme A20 requires RNF11 to downregulate NF-kappaB signalling. EMBO J. 2009 Mar 4;28(5):513-22. [Content Brief]

[6]. Tung-Liang Lee, et al. Itch regulates p45/NF-E2 in vivo by Lys63-linked ubiquitination. Biochem Biophys Res Commun. 2008 Oct 24;375(3):326-30. [Content Brief]

[7]. Chun Yang, et al. Negative regulation of the E3 ubiquitin ligase itch via Fyn-mediated tyrosine phosphorylation. Mol Cell. 2006 Jan 6;21(1):135-41. [Content Brief]

[8]. Loredana Puca, et al. Α-arrestin 1 (ARRDC1) and β-arrestins cooperate to mediate Notch degradation in mammals. J Cell Sci. 2013 Oct 1;126(Pt 19):4457-68. [Content Brief]

[9]. Patricia Chastagner, et al. Itch/AIP4 mediates Deltex degradation through the formation of K29-linked polyubiquitin chains. EMBO Rep. 2006 Nov;7(11):1147-53. [Content Brief]

[10]. Julia Mössinger, et al. Phosphatidylinositol 4-kinase IIα function at endosomes is regulated by the ubiquitin ligase Itch. EMBO Rep. 2012 Dec;13(12):1087-94. [Content Brief]

[11]. Takumi Tsunoda, et al. ENTREP/FAM189A2 encodes a new ITCH ubiquitin ligase activator that is downregulated in breast cancer. EMBO Rep. 2022 Feb 3;23(2):e51182. [Content Brief]

[12]. Mingfang Tao, et al. ITCH K63-ubiquitinates the NOD2 binding protein, RIP2, to influence inflammatory signaling pathways. Curr Biol. 2009 Aug 11;19(15):1255-63. [Content Brief]

[13]. Adriano Marchese, et al. The E3 ubiquitin ligase AIP4 mediates ubiquitination and sorting of the G protein-coupled receptor CXCR4. Dev Cell. 2003 Nov;5(5):709-22. [Content Brief]

[14]. Claudia Baumann, et al. The E3 ubiquitin ligase Itch regulates sorting nexin 9 through an unconventional substrate recognition domain. FEBS J. 2010 Jul;277(13):2803-14. [Content Brief]

[15]. Justine Holleman, et al. The ubiquitin ligase deltex-3l regulates endosomal sorting of the G protein-coupled receptor CXCR4. Mol Biol Cell. 2014 Jun 15;25(12):1892-904. [Content Brief]

[16]. Pingzhao Zhang, et al. The ubiquitin ligase itch regulates apoptosis by targeting thioredoxin-interacting protein for ubiquitin-dependent degradation. J Biol Chem. 2010 Mar 19;285(12):8869-79. [Content Brief]

[17]. G Winberg, et al. Latent membrane protein 2A of Epstein-Barr virus binds WW domain E3 protein-ubiquitin ligases that ubiquitinate B-cell tyrosine kinases. Mol Cell Biol. 2000 Nov;20(22):8526-35. [Content Brief]

[18]. Deepali Bhandari, et al. The E3 ubiquitin ligase atrophin interacting protein 4 binds directly to the chemokine receptor CXCR4 via a novel WW domain-mediated interaction. Mol Biol Cell. 2009 Mar;20(5):1324-39. [Content Brief]

[19]. Libing Feng, et al. Atrophin-1-interacting protein 4/human Itch is a ubiquitin E3 ligase for human enhancer of filamentation 1 in transforming growth factor-beta signaling pathways. J Biol Chem. 2004 Jul 9;279(28):29681-90. [Content Brief]

[20]. Bilal A Azakir, et al. The ubiquitin ligase Itch mediates the antiapoptotic activity of epidermal growth factor by promoting the ubiquitylation and degradation of the truncated C-terminal portion of Bid. FEBS J. 2010 Mar;277(5):1319-30. [Content Brief]

[21]. Ley-Hian Low, et al. Nedd4 family interacting protein 1 (Ndfip1) is required for ubiquitination and nuclear trafficking of BRCA1-associated ATM activator 1 (BRAT1) during the DNA damage response. J Biol Chem. 2015 Mar 13;290(11):7141-50. [Content Brief]

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