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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Neesar Ahmed
  • Minghui Zeng
  • Indrajit Sinha
  • Lisa Polin
  • Wei-Zen Wei
  • Chozhavendan Rathinam
  • Richard Flavell
  • Ramin Massoumi
  • K. Venuprasad
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
Original languageEnglish
Pages (from-to)1176-U1
JournalNature Immunology
Volume12
Issue number12
Publication statusPublished - 2011
Publication categoryResearch
Peer-reviewedYes