title: A combinatorial F box protein directed pathway controls TRAF adaptor stability to regulate inflammation.
abstract: Uncontrolled activation of tumor necrosis factor receptor-associated factor (TRAF) proteins may result in profound tissue injury by linking surface signals to cytokine release. Here we show that a ubiquitin E3 ligase component, Fbxo3, potently stimulates cytokine secretion from human inflammatory cells by destabilizing a sentinel TRAF inhibitor, Fbxl2. Fbxo3 and TRAF protein in circulation positively correlated with cytokine responses in subjects with sepsis, and we identified a polymorphism in human Fbxo3, with one variant being hypofunctional. A small-molecule inhibitor targeting Fbxo3 was sufficient to lessen severity of cytokine-driven inflammation in several mouse disease models. These studies identified a pathway of innate immunity that may be useful to detect subjects with altered immune responses during critical illness or provide a basis for therapeutic intervention targeting TRAF protein abundance.
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. chenb@upmc.edu
authors.forename: Bill B
authors.initials: BB
authors.lastname: Chen
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Coon
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Glasser
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: McVerry
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Yutong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Chunbin
authors.initials: C
authors.lastname: Zou
authors.forename: Bryon
authors.initials: B
authors.lastname: Ellis
authors.forename: Frank C
authors.initials: FC
authors.lastname: Sciurba
authors.forename: Yingze
authors.initials: Y
authors.lastname: Zhang
authors.forename: Rama K
authors.initials: RK
authors.lastname: Mallampalli
mesh_terms: D000818:Animals; D002432:Cecum / Q000276:immunology / Q000601:surgery; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D044782:F-Box Motifs / Q000235:genetics; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D056747:Immunomodulation; D007249:Inflammation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D011110:Polymorphism, Genetic; D055550:Protein Stability; D011552:Pseudomonas Infections / Q000235:genetics / Q000276:immunology*; D011550:Pseudomonas aeruginosa / Q000235:genetics / Q000276:immunology*; D034741:RNA, Small Interfering / Q000235:genetics; D018805:Sepsis / Q000235:genetics / Q000276:immunology*; D019076:Transgenes / Q000235:genetics; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism*
chemical_list: D016207:Cytokines; D044783:F-Box Proteins; D034741:RNA, Small Interfering; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; C533903:FBXO3 protein, human
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