Dendritic cells (DCs) are targets of measles virus (MV) and play central roles in viral dissemination. However, DCs express the RIG-I-like receptors (RLRs) RIG-I and Mda5 that sense MV and induce type I interferon (IFN) production. Given the potency of this antiviral response, RLRs are tightly regulated at various steps, including dephosphorylation by PP1 phosphatases, which induces their activation. We demonstrate that MV suppresses RIG-I and Mda5 by activating the C-type lectin DC-SIGN and inducing signaling that prevents RLR dephosphorylation. MV binding to DC-SIGN leads to activation of the kinase Raf-1, which induces the association of PP1 inhibitor I-1 with GADD34-PP1 holoenzymes, thereby inhibiting phosphatase activity. Consequently, GADD34-PP1 holoenzymes are unable to dephosphorylate RIG-I and Mda5, hence suppressing type I IFN responses and enhancing MV replication. Blocking DC-SIGN signaling allows RLR activation and suppresses MV infection of DCs. Thus, MV subverts DC-SIGN to control RLR activation and escape antiviral responses.
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