The E3 ligase Itch negatively regulates inflammatory signaling pathways by controlling the function of the ubiquitin-editing enzyme A20

Noula Shembade, Nicole S. Harhaj, Kislay Parvatiyar, Neal G. Copeland, Nancy A. Jenkins, Lydia E. Matesic, Edward Harhaj

Research output: Contribution to journalArticlepeer-review

207 Scopus citations

Abstract

The ubiquitin-editing enzyme A20 is a critical negative regulator of inflammation and cytokine-mediated activation of the transcription factor NF-κB; however, little is known about the mechanisms of A20-mediated inactivation of signaling intermediates such as RIP1. Here we demonstrate that the regulatory molecule TAX1BP1 recruited the E3 ligase Itch to A20 via two 'PPXY' motifs. Itch was essential for the termination of tumor necrosis factor receptor signaling by controlling A20-mediated recruitment and inactivation of RIP1. Furthermore, the Tax oncoprotein of human T cell leukemia virus type I targeted this complex for inactivation by disrupting the interaction among TAX1BP1, A20 and Itch. Thus, our studies show a previously unappreciated complexity of A20 substrate recognition and inactivation whereby TAX1BP1 and Itch function as essential subunits of an A20 ubiquitin-editing complex.

Original languageEnglish (US)
Pages (from-to)254-262
Number of pages9
JournalNature Immunology
Volume9
Issue number3
DOIs
StatePublished - Mar 1 2008

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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