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

Nat Immunol. 2013 May;14(5):470-9. doi: 10.1038/ni.2565. Epub 2013 Mar 31.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cecum / immunology
  • Cecum / surgery
  • Cell Line
  • Cytokines / metabolism
  • Disease Models, Animal
  • F-Box Motifs / genetics
  • F-Box Proteins / genetics
  • F-Box Proteins / metabolism*
  • Humans
  • Immunomodulation
  • Inflammation / genetics
  • Mice
  • Mice, Inbred C57BL
  • Polymorphism, Genetic
  • Protein Stability
  • Pseudomonas Infections / genetics
  • Pseudomonas Infections / immunology*
  • Pseudomonas aeruginosa / genetics
  • Pseudomonas aeruginosa / immunology*
  • RNA, Small Interfering / genetics
  • Sepsis / genetics
  • Sepsis / immunology*
  • Transgenes / genetics
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / metabolism*

Substances

  • Cytokines
  • F-Box Proteins
  • Fbx3 protein, human
  • RNA, Small Interfering
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins