Abstract 5395: 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. Our previous studies have achieved important new insights into key regulatory mechanism in the immune system mediated by the ubiquitin ligase, Itch, whose deficiency results in inflammatory disorders and pulmonary inflammation (Venuprasad K et al. Nat. Immunol. 2008, Venuprasad K. et al. J.Clin. Invest. 2004). We demonstrate that E3 ligase Itch and deubiquitinase Cyld formed a complex via interaction through ‘WW-PPXY’ motifs. The Itch-Cyld complex sequentially cleaved K63-linked ubiquitin chains and catalyzed Lys48-linked ubiquitination on TGF-beta activated kinase 1(Tak1) to terminate inflammatory signaling. Itch or Cyld deficiency resulted in sustained Tak1 activation and elevated production of proinflammatory cytokines by bone marrow derived macrophages (BMDMs). Tak1 selective inhibitor, (5Z)-7-Oxozeaenol abrogated Tak1 activation and production of proinflammatory cytokines by Itch-/- and Cyld-/- BMDMs. Similarly, ectopic expression of a catalytically inactive dominant-negative (Tak1-K63W) inhibited elevated cytokine production by Itch-/- and Cyld-/- BMDMs. 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 Cyldα/β BMDMs. 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. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5395. doi:1538-7445.AM2012-5395