The Ubiquitin Ligase Riplet Is Essential for RIG-I-Dependent Innate Immune Responses to RNA Virus Infection

RNA virus infection is recognized by the RIG-I-like receptors RIG-I and MDA5, which induce antiviral responses including the production of type I interferons (IFNs) and proinflammatory cytokines. RIG-I is regulated by Lys63-linked polyubiquitination, and three E3 ubiquitin ligases, RNF125, TRIM25, and Rip let, are reported to target RIG-I for ubiquitination. To examine the importance of Rip let in vivo, we generated Rip let-deficient mice. Fibroblasts, macrophages, and conventional dendritic cells from Riplet-deficient animals were defective for the production of IFN and other cytokines in response to infection with several RNA viruses. However, Rip let was dispensable for the production of IFN in response to B-DNA and DNA virus infection. Rip let deficiency abolished RIG-I activation during RNA virus infection, and the mutant mice were more susceptible to vesicular stomatitis virus infection than wild-type mice. These data indicate that Rip let is essential for regulating RIG-I-mediated innate immune response against RNA virus infection in vivo.