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

Authors
Journal
Nature Immunology
1529-2908
Publisher
Nature Publishing Group
Publication Date
Volume
14
Issue
5
Identifiers
DOI: 10.1038/ni.2565
Keywords
  • Article
Disciplines
  • Biology
  • Medicine

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 septic subjects and we furthermore identified a hypofunctional Fbxo3 human polymorphism. A small molecule inhibitor targeting Fbxo3 was sufficient to lessen severity of cytokine-driven inflammation in several murine disease models. These studies identify a pathway of innate immunity that may characterize subjects with altered immune responses during critical illness or provide a basis for therapeutic intervention targeting TRAF protein abundance.

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