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

In English

Författare

  • 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.

Avdelning/ar

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

Publiceringsår

2011

Språk

Engelska

Sidor

1-1176

Publikation/Tidskrift/Serie

Nature Immunology

Volym

12

Issue

12

Dokumenttyp

Artikel i tidskrift

Förlag

Nature Publishing Group

Ämne

  • Cancer and Oncology

Status

Published

Forskningsgrupp

  • Cell Pathology, Malmö

ISBN/ISSN/Övrigt

  • ISSN: 1529-2908