Activation of nucleic acid sensing cGAS-STING pathway by Sindbis Virus

Abstract

Cytosolic DNA sensing by cGAS plays an important role in type I interferon mediated antiviral immunity against DNA viruses or retroviruses. Second messenger cGAMP is produced from activated cGAS which binds to STING and leads to subsequent activation of type I interferon production cascade and antiviral response. Currently, only B form and Y form dsDNA as well as DNA:RNA hybrid have been considered as cGAS ligand. The role of cGAS in RNA virus sensing remains unclear. Here we explore the possible mode of cGAS activation by positive-sense single-stranded RNA virus, Sindbis virus. cGAS transcript was induced upon Sindbis virus infection and this induction was type I interferon signaling independent. Reconstitution of cGAS and STING in cGAS- and STING-null cells effectively suppresses Sindbis virus replication. On the other hand, loss of either cGAS or STING augmented Sindbis virus replication and prevented viral induction of type I interferon mediated antiviral immunity, suggesting a possible role of cGAS-STING signaling pathway in RNA viruses sensing. Enrichment of cytosolic nucleic acid species is observed in Sindbis virus-infected cells, indicating the presence of a cGAS ligand. Taken together, our findings reveal an unrecognized role of cGAS-STING pathway for cytosolic DNA sensing in RNA virus infection. Supported by HKRGC (HKU171091/14M and C7011-15R).