Research ArticleImmunology

The Tyrosine Kinase Syk Differentially Regulates Toll-like Receptor Signaling Downstream of the Adaptor Molecules TRAF6 and TRAF3

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Science Signaling  20 Aug 2013:
Vol. 6, Issue 289, pp. ra71
DOI: 10.1126/scisignal.2003973

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Syk Tunes TRAF Signaling

Toll-like receptor 4 (TLR4), a pattern recognition receptor that binds to the microbial product lipopolysaccharide (LPS), activates two signaling pathways involving protein ubiquitination that have opposing outcomes for the immune response. When at the plasma membrane, LPS-stimulated TLR4 associates with the adaptor MyD88 and the E3 ubiquitin ligase TRAF6 to stimulate production of proinflammatory cytokines. When internalized and localized in endosomes, TLR4 associates with the adaptor TRIF and the E3 ubiquitin ligase TRAF3 to stimulate production of immunomodulatory type I interferons. Lin et al. found that, although the nonreceptor tyrosine kinase Syk was recruited to both TRAF6- and TRAF3-containing signaling complexes, it led to differential regulation of TRAF ubiquitination such that TRAF6-dependent proinflammatory signaling was inhibited and TRAF3-dependent IFN production was enhanced. Experiments in Syk-deficient mouse macrophages showed that Syk had similar effects on TRAF6 and TRAF3 signaling downstream of other TLRs. Together, these data suggest that Syk can fine-tune innate immune responses to dampen inflammation.

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