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

作者：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^*

来源：Nature Immunology, 2013, 14(5): 470-+.

DOI：10.1038/ni.2565

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.

• 出版日期2013-5