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J. Biol. Chem., Vol. 283, Issue 11, 7036-7045, March 14, 2008

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NF-B Suppression by the Deubiquitinating Enzyme Cezanne

A NOVEL NEGATIVE FEEDBACK LOOP IN PRO-INFLAMMATORY SIGNALING^*

Karine Enesa, Mustafa Zakkar, Hera Chaudhury, Le A. Luong, Lesley Rawlinson, Justin C. Mason, Dorian O. Haskard, Jonathan L. E. Dean, and Paul C. Evans¹

From the British Heart Foundation Cardiovascular Sciences Unit, National Heart and Lung Institute, and the Kennedy Institute of Rheumatology Division, Imperial College London, London W12 ONN, United Kingdom

Transcription factors belonging to the NF-B family regulate inflammation by inducing pro-inflammatory molecules (e.g. interleukin (IL)-8) in response to cytokines (e.g. tumor necrosis factor (TNF) , IL-1) or other stimuli. Several negative regulators of NF-B, including the ubiquitin-editing enzyme A20, participate in the resolution of inflammatory responses. We report that Cezanne, a member of the A20 family of the deubiquitinating cysteine proteases, can be induced by TNF in cultured cells. Silencing of endogenous Cezanne using small interfering RNA led to elevated NF-B luciferase reporter gene activity and enhanced expression of IL-8 transcripts in TNF-treated cells. Thus we conclude that endogenous Cezanne can attenuate NF-B activation and the induction of pro-inflammatory transcripts in response to TNF receptor (TNFR) signaling. Overexpression studies revealed that Cezanne suppressed NF-B nuclear translocation and transcriptional activity by targeting the TNFR signaling pathway at the level of the IB kinase complex or upstream from it. These effects were not observed in a form of Cezanne that was mutated at the catalytic cysteine residue (Cys²⁰⁹), indicating that the deubiquitinating activity of Cezanne is essential for NF-B regulation. Finally, we demonstrate that Cezanne can be recruited to activated TNFRs where it suppresses the build-up of polyubiquitinated RIP1 signal adapter proteins. Thus we conclude that Cezanne forms a novel negative feedback loop in pro-inflammatory signaling and that it suppresses NF-B activation by targeting RIP1 signaling intermediaries for deubiquitination.

Received for publication, October 19, 2007 , and in revised form, December 18, 2007.

^* This work was supported by the British Heart Foundation, Kidney Research UK, and the National Heart and Lung Institute. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: Senior Lecturer, BHF Cardiovascular Sciences Unit, National Heart and Lung Institute, Imperial College London, Hammersmith Campus, Du Cane Rd., London W12 ONN, UK. Tel.: 44-20-83831619; Fax: 44-20-83831640; E-mail: paul.evans{at}imperial.ac.uk.

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