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

På svenska

Author

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

Summary, in English

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.

Department/s

  • Cell Pathology, Malmö
  • BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation

Publishing year

2011

Language

English

Pages

1-1176

Publication/Series

Nature Immunology

Volume

12

Issue

12

Document type

Journal article

Publisher

Nature Publishing Group

Topic

  • Cancer and Oncology

Status

Published

Research group

  • Cell Pathology, Malmö

ISBN/ISSN/Other

  • ISSN: 1529-2908