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 journalArticlepeer-review

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
Pages (from-to)1176-U1
JournalNature Immunology
Volume12
Issue number12
DOIs
Publication statusPublished - 2011

Subject classification (UKÄ)

  • Cancer and Oncology

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