Research ArticleImmunology

Ubiquitin-Specific Protease 25 Regulates TLR4-Dependent Innate Immune Responses Through Deubiquitination of the Adaptor Protein TRAF3

Sci. Signal.  14 May 2013:
Vol. 6, Issue 275, pp. ra35
DOI: 10.1126/scisignal.2003708

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Maintaining a Balanced Response

Activation of Toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS) stimulates two signaling pathways that are mediated by distinct adaptor proteins and depend on ubiquitination. The first, which requires the adaptor MyD88 (myeloid differentiation marker 88), results in production of proinflammatory cytokines, whereas the second, which involves the adaptors TRIF (Toll–interleukin-1 receptor domain–containing adaptor-inducing interferon-β) and TRAF3 (tumor necrosis factor receptor–associated factor 3), results in production of the modulatory cytokine interferon-α (IFN-α). Zhong et al. found that the deubiquitinase USP25 (ubiquitin-specific protease 25) was required for this second pathway. LPS stimulated the association of USP25 with TLR4 and TRAF3, and loss of USP25 resulted in enhanced ubiquitination and degradation of TRAF3 and inhibition of IFN-α production. As a result, USP25-deficient mice produced more inflammatory cytokines and less IFN-α and were more susceptible to death in response to LPS than were their wild-type counterparts. These data suggest that USP25 is required to maintain balanced TLR4 signaling and prevent an excessive inflammatory response.