ITCH explained

ITCH is a HECT domain–containing E3 ubiquitin ligase that is ablated in non-agouti-lethal 18H (aka Itchy) mice.[1] [2] Itchy mice develop a severe immunological phenotype after birth that includes hyperplasia of lymphoid and hematopoietic cells, and stomach and lung inflammation.[3] [4] In humans ITCH deficiency causes altered physical growth, craniofacial morphology defects, defective muscle development, and aberrant immune system function.[5] The ITCH gene is located on chromosome 20 in humans.[6] ITCH contains a C2 domain, proline-rich region, WW domains, HECT domain, and multiple amino acids that are phosphorylated and ubiquitinated.[7]

Regulation by phosphorylation

ITCH is regulated by MAPK8.[8] MAPK8 regulates JUNB protein turnover by MAPK8-dependent phosphorylation of ITCH and a subsequent conformational change in ITCH. This mechanism is discrete from the direct activation of Jun family transcription factors by direct phosphorylation. ITCH serves as a paradigm for our understanding of the regulation of the ubiquitylation machinery by direct protein phosphorylation of its components. Importantly, this regulatory process controls the balance of Th2 cytokine secretion by negatively regulating JUNB levels and Interleukin 4 transcription.[9]

Interaction partners

Itch has been shown to interact with a number of proteins,[10] including:

Notes and References

  1. Perry WL, Hustad CM, Swing DA, O'Sullivan TN, Jenkins NA, Copeland NG . The itchy locus encodes a novel ubiquitin protein ligase that is disrupted in a18H mice . Nature Genetics . 18 . 2 . 143–146 . February 1998 . 9462742 . 10.1038/ng0298-143 . 9438916 .
  2. Web site: Q96J02 | SWISS-MODEL Repository.
  3. Melino G, Gallagher E, Aqeilan RI, Knight R, Peschiaroli A, Rossi M, Scialpi F, Malatesta M, Zocchi L, Browne G, Ciechanover A, Bernassola F . Itch: a HECT-type E3 ligase regulating immunity, skin and cancer . Cell Death and Differentiation . 15 . 7 . 1103–1112 . July 2008 . 18552861 . 10.1038/cdd.2008.60 . 2626150 . free .
  4. Aki D, Zhang W, Liu YC . The E3 ligase Itch in immune regulation and beyond . Immunological Reviews . 266 . 1 . 6–26 . July 2015 . 26085204 . 10.1111/imr.12301 . 42110767 .
  5. 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 . American Journal of Human Genetics . 86 . 3 . 447–453 . March 2010 . 20170897 . 2833372 . 10.1016/j.ajhg.2010.01.028 .
  6. Web site: Symbol report for ITCH. HGNC. HUGO Gene Nomenclature Committee. 12 March 2024.
  7. Web site: ITCH (human). 2020-10-27. www.phosphosite.org.
  8. Karin M, Gallagher E . From JNK to pay dirt: jun kinases, their biochemistry, physiology and clinical importance . IUBMB Life . 57 . 4–5 . 283–295 . 2005 . 16036612 . 10.1080/15216540500097111 . 25508987 .
  9. Gao M, Karin M . Regulating the regulators: control of protein ubiquitination and ubiquitin-like modifications by extracellular stimuli . Molecular Cell . 19 . 5 . 581–593 . September 2005 . 16137616 . 10.1016/j.molcel.2005.08.017 . free .
  10. Web site: ITCH itchy E3 ubiquitin protein ligase [Homo sapiens (human)] - Gene - NCBI]. 2021-12-29. www.ncbi.nlm.nih.gov.
  11. Bhandari D, Robia SL, Marchese A . The E3 ubiquitin ligase atrophin interacting protein 4 binds directly to the chemokine receptor CXCR4 via a novel WW domain-mediated interaction . Molecular Biology of the Cell . 20 . 5 . 1324–1339 . March 2009 . 19116316 . 2649280 . 10.1091/mbc.e08-03-0308 .
  12. Fang D, Kerppola TK . Ubiquitin-mediated fluorescence complementation reveals that Jun ubiquitinated by Itch/AIP4 is localized to lysosomes . Proceedings of the National Academy of Sciences of the United States of America . 101 . 41 . 14782–14787 . October 2004 . 15469925 . 522008 . 10.1073/pnas.0404445101 . free . 2004PNAS..10114782F .
  13. Ahn YH, Kurie JM . MKK4/SEK1 is negatively regulated through a feedback loop involving the E3 ubiquitin ligase itch . The Journal of Biological Chemistry . 284 . 43 . 29399–29404 . October 2009 . 19737936 . 2785572 . 10.1074/jbc.M109.044958 . free .
  14. Enzler T, Chang X, Facchinetti V, Melino G, Karin M, Su B, Gallagher E . MEKK1 binds HECT E3 ligase Itch by its amino-terminal RING motif to regulate Th2 cytokine gene expression . Journal of Immunology . 183 . 6 . 3831–3838 . September 2009 . 19710465 . 10.4049/jimmunol.0803412 . 12554570 . free .
  15. Kathania M, Zeng M, Yadav VN, Moghaddam SJ, Yang B, Venuprasad K . Ndfip1 regulates itch ligase activity and airway inflammation via UbcH7 . Journal of Immunology . 194 . 5 . 2160–2167 . March 2015 . 25632008 . 10.4049/jimmunol.1402742 . 22850215 . free .
  16. Gallagher E, Gao M, Liu YC, Karin M . Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change . Proceedings of the National Academy of Sciences of the United States of America . 103 . 6 . 1717–1722 . February 2006 . 16446428 . 1413664 . 10.1073/pnas.0510664103 . free . 2006PNAS..103.1717G .
  17. Oberst A, Malatesta M, Aqeilan RI, Rossi M, Salomoni P, Murillas R, Sharma P, Kuehn MR, Oren M, Croce CM, Bernassola F, Melino G . The Nedd4-binding partner 1 (N4BP1) protein is an inhibitor of the E3 ligase Itch . Proceedings of the National Academy of Sciences of the United States of America . 104 . 27 . 11280–11285 . July 2007 . 17592138 . 2040890 . 10.1073/pnas.0701773104 . free . 2007PNAS..10411280O .
  18. Puca L, Chastagner P, Meas-Yedid V, Israël A, Brou C . Α-arrestin 1 (ARRDC1) and β-arrestins cooperate to mediate Notch degradation in mammals . Journal of Cell Science . 126 . Pt 19 . 4457–4468 . October 2013 . 23886940 . 10.1242/jcs.130500 . 9783441 . free .
  19. Rossi M, Aqeilan RI, Neale M, Candi E, Salomoni P, Knight RA, Croce CM, Melino G . The E3 ubiquitin ligase Itch controls the protein stability of p63 . Proceedings of the National Academy of Sciences of the United States of America . 103 . 34 . 12753–12758 . August 2006 . 16908849 . 1550770 . 10.1073/pnas.0603449103 . free . 2006PNAS..10312753R .
  20. Rossi M, De Laurenzi V, Munarriz E, Green DR, Liu YC, Vousden KH, Cesareni G, Melino G . The ubiquitin-protein ligase Itch regulates p73 stability . The EMBO Journal . 24 . 4 . 836–848 . February 2005 . 15678106 . 549609 . 10.1038/sj.emboj.7600444 .

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