The E3 ligase Itch and deubiquitinase Cyld act together to regulate Tak1 and inflammation

Neesar Ahmed, Minghui Zeng, Indrajit Sinha, Lisa Polin, Wei Zen Wei, Chozhavendan Rathinam, Richard Flavell, Ramin Massoumi, K. Venuprasad

Research output: Contribution to journalArticle

85 Scopus citations

Abstract

Chronic inflammation has been strongly associated with tumor progression, but the underlying mechanisms remain elusive. Here we demonstrate that E3 ligase Itch and deubiquitinase Cyld formed a complex via interaction through 'WW-PPXY' motifs. The Itch-Cyld complex sequentially cleaved Lys63-linked ubiquitin chains and catalyzed Lys48-linked ubiquitination on the kinase Tak1 to terminate inflammatory signaling via tumor necrosis factor. Reconstitution of wild-type Cyld but not the mutant Cyld(Y485A), which cannot associate with Itch, blocked sustained Tak1 activation and proinflammatory cytokine production by Cyld -/- bone marrow-derived macrophages. Deficiency in Itch or Cyld led to chronic production of tumor-promoting cytokines by tumor-associated macrophages and aggressive growth of lung carcinoma. Thus, we have identified an Itch-Cyld-mediated regulatory mechanism in innate inflammatory cells.

Original languageEnglish (US)
Pages (from-to)1176-1183
Number of pages8
JournalNature immunology
Volume12
Issue number12
DOIs
StatePublished - Dec 1 2011
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Ahmed, N., Zeng, M., Sinha, I., Polin, L., Wei, W. Z., Rathinam, C., Flavell, R., Massoumi, R., & Venuprasad, K. (2011). The E3 ligase Itch and deubiquitinase Cyld act together to regulate Tak1 and inflammation. Nature immunology, 12(12), 1176-1183. https://doi.org/10.1038/ni.2157