Synaptogyrin-2 Promotes Replication and Immune Evasion of A Novel Tick-borne Bunyavirus through Interacting with Viral Nonstructural Protein NSs

Abstract

Abstract Synaptogyrin-2 is a non-neuronal member of the synaptogyrin family involved in synaptic vesicle biogenesis and trafficking. Little has been known about the function of synaptogyrin-2. Severe Fever with Thrombocytopenia Syndrome (SFTS) is an emerging infectious disease characterized by high fever, thrombocytopenia, and leukocytopenia with a high fatality and caused by a novel tick-borne phlebovirus in the family Bunyaviridae. Our previous studies have shown that viral nonstructural protein NSs formed inclusion bodies (IBs) which are involved in viral immune evasion as well as in viral RNA replication. In this report, we sought to elucidate the mechanism how NSs formed the IBs, a lipid droplet-based structure confirmed by NSs co-localization with perilipin A and ADRP. We identified synaptogyrin-2 to be highly upregulated in response to SFTS bunyavirus (SFTSV) infection through a high throughput screening and be a promoter of viral replication. We demonstrated that synaptogyrin-2 interacted with NSs and was translocated into the IBs, which were reconstructed from lipid droplets into large structures in infection. Viral RNA replication decreased and infectious virus titers were lowered significantly when synaptogyrin-2 was silenced in specific shRNA-expressing cells, which was in parallel to the reduced number of the large IBs restructured from regular lipid droplets and increased antiviral interferon induction. We hypothesize that synaptogyrin-2 is essential to promoting the formation of the IBs, to be virus factories for viral RNA replication and immune evasion through its interaction with NSs. The findings unveiled the function of synaptogyrin-2 as an enhancer in viral infection.