Host MOV10 is induced to restrict herpes simplex virus 1 lytic infection by promoting type I interferon response

Moloney leukemia virus 10 protein (MOV10) is an IFN-inducible RNA helicase implicated in antiviral activity against RNA viruses, yet its role in herpesvirus infection has not been investigated. After corneal inoculation of mice with herpes simplex virus 1 (HSV-1), we observed strong upregulation of both MOV10 mRNA and protein in acutely infected mouse trigeminal ganglia. MOV10 suppressed HSV-1 replication in both neuronal and non-neuronal cells, and this suppression required the N-terminus, but not C-terminal helicase domain of MOV10. MOV10 repressed expression of the viral gene ICP0 in transfected cells, but suppressed HSV-1 replication independently of ICP0. MOV10 increased expression of type I IFN in HSV-1 infected cells with little effect on IFN downstream signaling. Treating the cells with IFN-alpha or an inhibitor of the IFN receptor eliminated MOV10 suppression of HSV-1 replication. MOV10 enhanced IFN production stimulated by cytoplasmic RNA rather than DNA. IKK epsilon co-immunoprecipitated with MOV10 and was required for MOV10 restriction of HSV-1 replication. Mass spectrometry identified ICP27 as a viral protein interacting with MOV10. Co-immunoprecipitation results suggested that this interaction depended on the RGG box of ICP27 and both termini of MOV10. Overexpressed ICP27, but not its RGG-Box deletion mutant, rendered MOV10 unable to regulate HSV-1 replication and type I IFN production. In summary, MOV10 is induced to restrict HSV-1 lytic infection by promoting the type I IFN response through an IKK epsilon -mediated RNA sensing pathway, and its activity is potentially antagonized by ICP27 in an RGG box dependent manner. Author summary Herpes simplex virus 1 (HSV-1) is a ubiquitous DNA virus that can cause various human diseases. Upon HSV-1 invasion, the host elicited the type I interferon (IFN) response as the first line of defense, in which numerous host factors are induced to restrict viral infection, yet our knowledge about these restriction factors remains limited. Here we show that during HSV-1 acute infection Moloney leukemia virus 10 protein (MOV10) was induced to restrict HSV-1 productive infection. MOV10 restricted HSV-1 replication by promoting type I IFN production through an IKK epsilon -mediated RNA sensing pathway. Moreover, we identified ICP27 as a viral protein that can interact with MOV10 and antagonize its antiviral activity. Thus we establish MOV10 as a host restriction factor against a herpesvirus for the first time and expand our knowledge about how viral and host proteins modulate the IFN response.