A combinatorial F box protein directed pathway controls TRAF adaptor stability to regulate inflammation.
Nat Immunol
; 14(5): 470-9, 2013 May.
Article
em En
| MEDLINE
| ID: mdl-23542741
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.
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Base de dados:
MEDLINE
Assunto principal:
Pseudomonas aeruginosa
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Infecções por Pseudomonas
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Sepse
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Proteínas F-Box
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Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article