IFN-stimulated P2Y₁₃ protects mice from viral infection by suppressing the cAMP/EPAC1 signaling pathway

Among the most important sensors of extracellular danger signals, purinergic receptors have been demonstrated to play crucial roles in host defense against infection. However, the function of P2 receptors in viral infection has been little explored. Here we demonstrated that P2Y₁₃ and its ligand ADP play an important role in protecting hosts from viral infections. First, we demonstrate that P2Y₁₃, as a typical interferon-stimulated gene, is induced together with extracellular ADP during viral infection. Most importantly, extracellular ADP restricts the replication of different kinds of viruses, including vesicular stomatitis virus, Newcastle disease virus, herpes simplex virus 1, and murine leukemia virus. This kind of protection is dependent on P2Y₁₃ but not P2Y₁ or P2Y₁₂, which are also considered as receptors for ADP. Furthermore, cyclic adenosine monophosphate and EPAC1 are downregulated by extracellular ADP through the P2Y₁₃-coupled Gi alpha subunit. Accordingly, inhibition or deletion of EPAC1 significantly eliminates ADP/P2Y₁₃-mediated antiviral activities. Taken together, our results show that P2Y₁₃ and ADP play pivotal roles in the clearance of invaded virus and have the potential as antiviral targets.