Research ArticleImmunology

The Ubiquitin-Specific Protease USP15 Promotes RIG-I–Mediated Antiviral Signaling by Deubiquitylating TRIM25

Sci. Signal.  07 Jan 2014:
Vol. 7, Issue 307, pp. ra3
DOI: 10.1126/scisignal.2004577

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Prolonging Antiviral Signaling

As part of the innate immune response to infection by RNA viruses, signaling by the cytosolic RNA sensor retinoic acid–inducible gene-I (RIG-I) stimulates the production of type I interferons (IFNs). RIG-I activity depends on its Lys63-linked polyubiquitylation by the ubiquitin E3 ligase TRIM25. As part of a negative feedback mechanism, the linear ubiquitin assembly complex (LUBAC) mediates the Lys48-linked polyubiquitylation and degradation of TRIM25, leading to inhibition of RIG-I signaling. Pauli et al. found that the deubiquitylase USP15 (ubiquitin-specific protease 15) counteracted the function of LUBAC by removing polyubiquitin from TRIM25, thus promoting its stabilization and enhancing the RIG-I–dependent antiviral response. Loss of USP15 resulted in decreased type I IFN production and enhanced viral replication in infected cells. Together, these data suggest that USP15 fine-tunes the antiviral response by sustaining the production of IFNs.