VAMP5 is an intrinsic defense factor for embryonic stem cells against SARS-CoV-2 infection

Stem cells are highly resistant to viral infection relying on intrinsic defense factor. Understanding their cell-autonomous protective effects to viruses infection provides new strategy of developing broad-spectrum antiviral treatments. Here we identified VAMP5, as a potent cell-autonomous defense factor against SARS-CoV-2 infection, highly expresses in ESCs and mesodermal cells. VAMP5 not only restricts SARS-CoV-2 wild-type and variants and other highly pathogenic coronaviruses replication, but also effectively against other virus families replication. Remarkably, VAMP5 also maintains stemness of ESCs and is required for ESCs differentiation. Mechanistic studies represented that VAMP5 locates at the DMV and restricts viral infection relying on its vesicle side of C-terminal domain to interact with viral NSP8 protein, resulting in the forbidden of synthesizing negative strand RNA. Based on our mechanistic studies, we suppose that VAMP5 in ESCs overcomes the protected environment of viral genome replication in DMV and interacts with RNA replication complexes to defense viral infection.