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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.

SUBMITTER: Chen BB 

PROVIDER: S-EPMC3631463 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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

Chen Bill B BB   Coon Tiffany A TA   Glasser Jennifer R JR   McVerry Bryan J BJ   Zhao Jing J   Zhao Yutong Y   Zou Chunbin C   Ellis Bryon B   Sciurba Frank C FC   Zhang Yingze Y   Mallampalli Rama K RK  

Nature immunology 20130331 5


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  ...[more]

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