| Structural highlights
Disease
[ITCH_HUMAN] Defects in ITCH are the cause of syndromic multisystem autoimmune disease (SMAD) [MIM:613385]. SMAD is characterized by organomegaly, failure to thrive, developmental delay, dysmorphic features and autoimmune inflammatory cell infiltration of the lungs, liver and gut.[1]
Function
[ITCH_HUMAN] 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. It catalyzes 'Lys-29'-, 'Lys-48'- and 'Lys-63'-linked ubiquitin conjugation. It is involved in the control of inflammatory signaling pathways. Is an 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. Critical regulator of T-helper (TH2) cytokine development through its ability to induce JUNB ubiquitination and degradation (By similarity). Ubiquitinates SNX9. Ubiquitinates CXCR4 and HGS/HRS and regulates sorting of CXCR4 to the degradative pathway. It is involved in the negative regulation of MAVS-dependent cellular antiviral responses. Ubiquitinates MAVS through 'Lys-48'-linked conjugation resulting in MAVS proteasomal degradation. 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. Targets DTX1 for lysosomal degradation and controls NOTCH1 degradation, in the absence of ligand, through 'Lys-29'-linked polyubiquitination.[2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [TXNIP_HUMAN] May act as an oxidative stress mediator by inhibiting thioredoxin activity or by limiting its bioavailability. Interacts with COPS5 and restores COPS5-induced suppression of CDKN1B stability, blocking the COPS5-mediated translocation of CDKN1B from the nucleus to the cytoplasm. Functions as a transcriptional repressor, possibly by acting as a bridge molecule between transcription factors and corepressor complexes, and over-expression will induce G0/G1 cell cycle arrest. Required for the maturation of natural killer cells. Acts as a suppressor of tumor cell growth. Inhibits the proteasomal degradation of DDIT4, and thereby contributes to the inhibition of the mammalian target of rapamycin complex 1 (mTORC1).[13] [14] [15] [16]
Publication Abstract from PubMed
Thioredoxin interacting protein (TXNIP) negatively regulates the antioxidative activity of thioredoxin, and participates in pleiotropic cellular processes. Its deregulation is linked to various human diseases including diabetes, acute myeloid leukemia and cardiovascular diseases. The E3 ubiquitin ligase Itch polyubiquitinates TXNIP to promote its degradation via the ubiquitin proteasome pathway, and this Itch-mediated poly-ubiquitination of TXNIP is dependent on the interaction of the four WW domains of Itch with the two PPxY motifs of TXNIP. However, the molecular mechanism of this interaction of TXNIP with Itch remains elusive. In this study, we found that each of the four WW domains of Itch exhibited different binding affinities to TXNIP, while multivalent engagement between the four WW domains of Itch and the two PPxY motifs of TXNIP resulted in their strong binding avidity. Our structural analyses demonstrated that the third and fourth WW domains of Itch were able to recognize both PPxY motifs of TXNIP simultaneously, supporting a multivalent binding mode between Itch and TXNIP. Interestingly, phosphorylation status on the tyrosine residue of the PPxY motifs of TXNIP serves as a molecular switch in its choice of binding partners and thereby downstream biological signaling outcomes. Phosphorylation of this tyrosine residue of TXNIP diminished the binding capability of PPxY motifs of TXNIP to Itch, whereas this phosphorylation is a prerequisite to the binding activity of TXNIP to SH2 domain containing protein SHP2 and their roles in stabilizing the phosphorylation and activation of CSK.
Structural basis for the regulatory role of the PPxY motifs in the thioredoxin-interacting protein TXNIP.,Liu Y, Lau J, Li W, Tempel W, Li L, Dong A, Narula A, Qin S, Min J Biochem J. 2015 Nov 2. pii: BJ20150830. PMID:26527736[17]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Lohr NJ, Molleston JP, Strauss KA, Torres-Martinez W, Sherman EA, Squires RH, Rider NL, Chikwava KR, Cummings OW, Morton DH, Puffenberger EG. Human ITCH E3 ubiquitin ligase deficiency causes syndromic multisystem autoimmune disease. Am J Hum Genet. 2010 Mar 12;86(3):447-53. doi: 10.1016/j.ajhg.2010.01.028. Epub, 2010 Feb 18. PMID:20170897 doi:10.1016/j.ajhg.2010.01.028
- ↑ Marchese A, Raiborg C, Santini F, Keen JH, Stenmark H, Benovic JL. The E3 ubiquitin ligase AIP4 mediates ubiquitination and sorting of the G protein-coupled receptor CXCR4. Dev Cell. 2003 Nov;5(5):709-22. PMID:14602072
- ↑ Chastagner P, Israel A, Brou C. Itch/AIP4 mediates Deltex degradation through the formation of K29-linked polyubiquitin chains. EMBO Rep. 2006 Nov;7(11):1147-53. Epub 2006 Oct 6. PMID:17028573 doi:10.1038/sj.embor.7400822
- ↑ Yang C, Zhou W, Jeon MS, Demydenko D, Harada Y, Zhou H, Liu YC. Negative regulation of the E3 ubiquitin ligase itch via Fyn-mediated tyrosine phosphorylation. Mol Cell. 2006 Jan 6;21(1):135-41. PMID:16387660 doi:10.1016/j.molcel.2005.11.014
- ↑ Lee TL, Shyu YC, Hsu TY, Shen CK. Itch regulates p45/NF-E2 in vivo by Lys63-linked ubiquitination. Biochem Biophys Res Commun. 2008 Oct 24;375(3):326-30. doi:, 10.1016/j.bbrc.2008.07.164. Epub 2008 Aug 19. PMID:18718448 doi:10.1016/j.bbrc.2008.07.164
- ↑ Scialpi F, Malatesta M, Peschiaroli A, Rossi M, Melino G, Bernassola F. Itch self-polyubiquitylation occurs through lysine-63 linkages. Biochem Pharmacol. 2008 Dec 1;76(11):1515-21. doi: 10.1016/j.bcp.2008.07.028., Epub 2008 Jul 31. PMID:18718449 doi:10.1016/j.bcp.2008.07.028
- ↑ Chastagner P, Israel A, Brou C. AIP4/Itch regulates Notch receptor degradation in the absence of ligand. PLoS One. 2008 Jul 16;3(7):e2735. doi: 10.1371/journal.pone.0002735. PMID:18628966 doi:10.1371/journal.pone.0002735
- ↑ Tao M, Scacheri PC, Marinis JM, Harhaj EW, Matesic LE, Abbott DW. ITCH K63-ubiquitinates the NOD2 binding protein, RIP2, to influence inflammatory signaling pathways. Curr Biol. 2009 Aug 11;19(15):1255-63. doi: 10.1016/j.cub.2009.06.038. Epub 2009 , Jul 9. PMID:19592251 doi:10.1016/j.cub.2009.06.038
- ↑ Shembade N, Parvatiyar K, Harhaj NS, Harhaj EW. The ubiquitin-editing enzyme A20 requires RNF11 to downregulate NF-kappaB signalling. EMBO J. 2009 Mar 4;28(5):513-22. doi: 10.1038/emboj.2008.285. Epub 2009 Jan 8. PMID:19131965 doi:10.1038/emboj.2008.285
- ↑ You F, Sun H, Zhou X, Sun W, Liang S, Zhai Z, Jiang Z. PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin ligase AIP4. Nat Immunol. 2009 Dec;10(12):1300-8. doi: 10.1038/ni.1815. Epub 2009 Nov 1. PMID:19881509 doi:10.1038/ni.1815
- ↑ Azakir BA, Desrochers G, Angers A. 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. doi: 10.1111/j.1742-4658.2010.07562.x. PMID:20392206 doi:10.1111/j.1742-4658.2010.07562.x
- ↑ Zhang P, Wang C, Gao K, Wang D, Mao J, An J, Xu C, Wu D, Yu H, Liu JO, Yu L. 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. doi: 10.1074/jbc.M109.063321. Epub 2010, Jan 12. PMID:20068034 doi:10.1074/jbc.M109.063321
- ↑ Liyanage NP, Fernando MR, Lou MF. Regulation of the bioavailability of thioredoxin in the lens by a specific thioredoxin-binding protein (TBP-2). Exp Eye Res. 2007 Aug;85(2):270-9. Epub 2007 May 21. PMID:17603038 doi:S0014-4835(07)00133-9
- ↑ Han SH, Jeon JH, Ju HR, Jung U, Kim KY, Yoo HS, Lee YH, Song KS, Hwang HM, Na YS, Yang Y, Lee KN, Choi I. VDUP1 upregulated by TGF-beta1 and 1,25-dihydorxyvitamin D3 inhibits tumor cell growth by blocking cell-cycle progression. Oncogene. 2003 Jun 26;22(26):4035-46. PMID:12821938 doi:10.1038/sj.onc.1206610
- ↑ Shin KH, Kim RH, Kim RH, Kang MK, Park NH. hnRNP G elicits tumor-suppressive activity in part by upregulating the expression of Txnip. Biochem Biophys Res Commun. 2008 Aug 8;372(4):880-5. doi:, 10.1016/j.bbrc.2008.05.175. Epub 2008 Jun 9. PMID:18541147 doi:10.1016/j.bbrc.2008.05.175
- ↑ Jin HO, Seo SK, Kim YS, Woo SH, Lee KH, Yi JY, Lee SJ, Choe TB, Lee JH, An S, Hong SI, Park IC. TXNIP potentiates Redd1-induced mTOR suppression through stabilization of Redd1. Oncogene. 2011 Sep 1;30(35):3792-801. doi: 10.1038/onc.2011.102. Epub 2011 Apr 4. PMID:21460850 doi:10.1038/onc.2011.102
- ↑ Liu Y, Lau J, Li W, Tempel W, Li L, Dong A, Narula A, Qin S, Min J. Structural basis for the regulatory role of the PPxY motifs in the thioredoxin-interacting protein TXNIP. Biochem J. 2015 Nov 2. pii: BJ20150830. PMID:26527736 doi:http://dx.doi.org/10.1042/BJ20150830
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