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.
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Acknowledgements
We thank W.C. Hahn (Dana-Farber Cancer Institute, Boston) for Myc-Cyld; J. Ashwell (US National Cancer Institute) for HA-tagged TRAF2Δ; A. Raz (Karmanos Cancer Institute) for pET30a; and Y.-C.M. Kong and R. Mathur for discussions. Supported by the US National Cancer Institute (1RC1CA146576-01 to K.V.).
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N.A., M.Z. and I.S. did the experiments and analyzed data; L.P. assisted with in vivo tumor studies; W.-Z.W. assisted in manuscript preparation; C.R. and R.F. provided critical reagents and mouse model; R.M. provided critical mouse model and assisted in manuscript preparation; and K.V. designed the experiments, analyzed data and wrote the manuscript.
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Ahmed, N., Zeng, M., Sinha, I. et al. The E3 ligase Itch and deubiquitinase Cyld act together to regulate Tak1 and inflammation. Nat Immunol 12, 1176–1183 (2011). https://doi.org/10.1038/ni.2157
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DOI: https://doi.org/10.1038/ni.2157
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