A combinatorial F box protein directed pathway controls TRAF adaptor stability to regulate inflammation

• Published in: Nature immunology Vol. 14; no. 5; pp. 470 - 479
• Main Authors: Chen, Bill B, Coon, Tiffany A, Glasser, Jennifer R, McVerry, Bryan J, Zhao, Jing, Zhao, Yutong, Zou, Chunbin, Ellis, Bryon, Sciurba, Frank C, Zhang, Yingze, Mallampalli, Rama K
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2013; Nature Publishing Group
• Subjects: 631/250/256; 631/250/516; 692/420/256/1980; Animals; Biomedicine; Cecum - immunology; Cecum - surgery; Cell Line; Cell receptors; Cytokines; Cytokines - metabolism; Development and progression; Disease Models, Animal; F-Box Motifs - genetics; F-Box Proteins - genetics; F-Box Proteins - metabolism; Genetic aspects; Humans; Immunology; Immunomodulation; Infectious Diseases; Inflammation; Inflammation - genetics; Mice; Mice, Inbred C57BL; Physiological aspects; Polymorphism, Genetic; Protein Stability; Pseudomonas aeruginosa - genetics; Pseudomonas aeruginosa - immunology; Pseudomonas Infections - genetics; Pseudomonas Infections - immunology; RNA, Small Interfering - genetics; Sepsis - genetics; Sepsis - immunology; Transgenes - genetics; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins - metabolism; United States
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.2565

Inflammation needs to be tightly regulated to avoid immunopathology. Mallampalli and colleagues show that a system of F box proteins tunes proinflammatory signaling by degrading TRAF adaptor proteins. 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.