RIG-I and Mda5 are key cytosolic sensors for the detection of RNA viruses and the production of interferon. In Immunity, Wies et al. show that Mda5 activation is regulated by a dynamic balance between phosphorylation and dephosphorylation of its N-terminal CARD domains. Phosphorylation of Mda5 at Ser88 residue under normal conditions suppresses interaction of Mda5 with MAVS. The phosphatases PP1α and PP1γ specifically dephosphorylate this residue, as well as Ser8 in RIG-I, to induce MAVS-CARD interactions, downstream signaling and interferon production. Virus infection triggers the recruitment of PP1α and PP1γ to Mda5 and RIG-I. Overexpression or depletion of the two phosphatases, which have additive effects, modulates the efficiency of viral replication in infected cells. These results add phosphorylation to the list of post-translational modifications that control the activity of RIG-I-like receptors.

Immunity 38, 437–449 (2013)