期刊
NATURE IMMUNOLOGY
卷 14, 期 5, 页码 470-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ni.2565
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资金
- US Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development
- Merit Review Award from the US Department of Veterans Affairs
- National Institutes [HL096376, HL097376, HL081784, HL068135, HL098174, HL116472, HL01916, P50HL084948]
- American Heart Association [12SDG9050005, 12SDG12040330, 12GRNT11820019]
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.
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