title: Cezanne regulates inflammatory responses to hypoxia in endothelial cells by targeting TRAF6 for deubiquitination.
abstract: BACKGROUND
  Hypoxia followed by reoxygenation promotes inflammation by activating nuclear factor κB transcription factors in endothelial cells (ECs). This process involves modification of the signaling intermediary tumor necrosis factor receptor-associated factor 6 with polyubiquitin chains. Thus, cellular mechanisms that suppress tumor necrosis factor receptor-associated factor 6 ubiquitination are potential therapeutic targets to reduce inflammation in hypoxic tissues.
  
  
  OBJECTIVE
  In this study, we tested the hypothesis that endothelial activation in response to hypoxia-reoxygenation can be influenced by Cezanne, a deubiquitinating enzyme that cleaves ubiquitin from specific modified proteins.
  
  
  RESULTS
  Studies of cultured ECs demonstrated that hypoxia (1% oxygen) induced Cezanne via p38 mitogen-activated protein kinase-dependent transcriptional and post-transcriptional mechanisms. Hypoxia-reoxygenation had minimal effects on proinflammatory signaling in unmanipulated ECs but significantly enhanced Lys63 polyubiquitination of tumor necrosis factor receptor-associated factor 6, activation of nuclear factor κB, and expression of inflammatory genes after silencing of Cezanne. Thus, although hypoxia primed cells for inflammatory activation, it simultaneously induced Cezanne, which impeded signaling to nuclear factor κB by suppressing tumor necrosis factor receptor-associated factor 6 ubiquitination. Similarly, ischemia induced Cezanne in the murine kidney in vascular ECs, glomerular ECs, podocytes, and epithelial cells, and genetic deletion of Cezanne enhanced renal inflammation and injury in murine kidneys exposed to ischemia followed by reperfusion.
  
  
  CONCLUSIONS
  We conclude that inflammatory responses to ischemia are controlled by a balance between ubiquitination and deubiquitination, and that Cezanne is a key regulator of this process. Our observations have important implications for therapeutic targeting of inflammation and injury during ischemia-reperfusion.
authors.affiliation: Department of Cardiovascular Science, University of Sheffield, Sheffield S10 2RX, UK.
authors.forename: Le A
authors.initials: le A
authors.lastname: Luong
authors.forename: Maria
authors.initials: M
authors.lastname: Fragiadaki
authors.forename: Jennifer
authors.initials: J
authors.lastname: Smith
authors.forename: Joseph
authors.initials: J
authors.lastname: Boyle
authors.forename: Jens
authors.initials: J
authors.lastname: Lutz
authors.forename: Jonathan L E
authors.initials: JL
authors.lastname: Dean
authors.forename: Sarah
authors.initials: S
authors.lastname: Harten
authors.forename: Margaret
authors.initials: M
authors.lastname: Ashcroft
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Walmsley
authors.forename: Dorian O
authors.initials: DO
authors.lastname: Haskard
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Maxwell
authors.forename: Henning
authors.initials: H
authors.lastname: Walczak
authors.forename: Charles
authors.initials: C
authors.lastname: Pusey
authors.forename: Paul C
authors.initials: PC
authors.lastname: Evans
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000201:enzymology* / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000098:blood supply*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D011916:Rats, Inbred F344; D015427:Reperfusion Injury / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D054875:Ubiquitination; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000072017:Deubiquitinating Enzymes
chemical_list: D010450:Endopeptidases; D018836:Inflammation Mediators; D016328:NF-kappa B; D010100:Oxygen; D048029:TNF Receptor-Associated Factor 6; D048051:p38 Mitogen-Activated Protein Kinases; C476458:OTUD7B protein, human; C582882:OTUD7B protein, rat; C578787:Otud7b protein, mouse; D000072017:Deubiquitinating Enzymes
keywords: endothelium; hypoxia; inflammatory activation
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