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

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


  • Ahmed N
  • Zeng M
  • Sinha I
  • Polin L
  • Wei WZ
  • Rathinam C
  • Flavell R
  • Massoumi R
  • Venuprasad K


Nature immunology

Publication Data

December 17, 2011

Associated Grants

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

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