| First Author | Chen BB | Year | 2013 |
| Journal | Nat Immunol | Volume | 14 |
| Issue | 5 | Pages | 470-9 |
| PubMed ID | 23542741 | Mgi Jnum | J:196439 |
| Mgi Id | MGI:5488521 | Doi | 10.1038/ni.2565 |
| Citation | Chen BB, et al. (2013) A combinatorial F box protein directed pathway controls TRAF adaptor stability to regulate inflammation. Nat Immunol 14(5):470-9 |
| abstractText | 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. |
