NF-kappaB suppression by the deubiquitinating enzyme Cezanne: a novel negative feedback loop in pro-inflammatory signaling

Transcription factors belonging to the NF-kappaB family regulate inflammation by inducing pro-inflammatory molecules (e.g. interleukin (IL)-8) in response to cytokines (e.g. tumor necrosis factor (TNF) alpha, IL-1) or other stimuli. Several negative regulators of NF-kappaB, including the ubiquitin-e...

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Veröffentlicht in:The Journal of biological chemistry 2008-03, Vol.283 (11), p.7036-7045
Hauptverfasser: Enesa, Karine, Zakkar, Mustafa, Chaudhury, Hera, Luong, Le A, Rawlinson, Lesley, Mason, Justin C, Haskard, Dorian O, Dean, Jonathan L E, Evans, Paul C
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container_end_page 7045
container_issue 11
container_start_page 7036
container_title The Journal of biological chemistry
container_volume 283
creator Enesa, Karine
Zakkar, Mustafa
Chaudhury, Hera
Luong, Le A
Rawlinson, Lesley
Mason, Justin C
Haskard, Dorian O
Dean, Jonathan L E
Evans, Paul C
description Transcription factors belonging to the NF-kappaB family regulate inflammation by inducing pro-inflammatory molecules (e.g. interleukin (IL)-8) in response to cytokines (e.g. tumor necrosis factor (TNF) alpha, IL-1) or other stimuli. Several negative regulators of NF-kappaB, 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 TNFalpha in cultured cells. Silencing of endogenous Cezanne using small interfering RNA led to elevated NF-kappaB luciferase reporter gene activity and enhanced expression of IL-8 transcripts in TNFalpha-treated cells. Thus we conclude that endogenous Cezanne can attenuate NF-kappaB activation and the induction of pro-inflammatory transcripts in response to TNF receptor (TNFR) signaling. Overexpression studies revealed that Cezanne suppressed NF-kappaB nuclear translocation and transcriptional activity by targeting the TNFR signaling pathway at the level of the IkappaB 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-kappaB 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-kappaB activation by targeting RIP1 signaling intermediaries for deubiquitination.
doi_str_mv 10.1074/jbc.M708690200
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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-kappaB regulation. Finally, we demonstrate that Cezanne can be recruited to activated TNFRs where it suppresses the build-up of polyubiquitinated RIP1 signal adapter proteins. 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subjects DNA-Binding Proteins
Endopeptidases - metabolism
Endothelial Cells - cytology
Gene Expression Regulation, Enzymologic
Humans
Inflammation
Interleukin-8 - metabolism
Intracellular Signaling Peptides and Proteins - metabolism
Lysine - chemistry
Models, Biological
Mutation
NF-kappa B - metabolism
Nuclear Pore Complex Proteins - metabolism
Nuclear Proteins - metabolism
Receptors, Tumor Necrosis Factor - metabolism
RNA-Binding Proteins - metabolism
Signal Transduction
Tumor Necrosis Factor alpha-Induced Protein 3
Ubiquitin - metabolism
title NF-kappaB suppression by the deubiquitinating enzyme Cezanne: a novel negative feedback loop in pro-inflammatory signaling
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