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

Nature immunology | Nov 6, 2011

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.

Pubmed ID: 22057290 RIS Download

Mesh terms: Amino Acid Motifs | Amino Acid Sequence | Animals | Binding Sites | Cell Line, Transformed | Cell Line, Tumor | Cysteine Endopeptidases | Enzyme Activation | HEK293 Cells | Humans | Inflammation | Inflammation Mediators | MAP Kinase Kinase Kinases | Macrophages | Mice | Mice, Inbred C57BL | Mice, Knockout | Molecular Sequence Data | Neoplasms | Protein Binding | Sequence Alignment | Ubiquitin-Protein Ligases | Ubiquitination

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Associated grants

  • Agency: NCI NIH HHS, Id: RC1 CA146576
  • Agency: NCI NIH HHS, Id: RC1 CA146576-01
  • Agency: NCI NIH HHS, Id: RC1 CA146576-02
  • Agency: NCI NIH HHS, Id: 1RC1CA146576-01

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