Kaposi's sarcoma-associated herpesvirus induces mitochondrial fission to evade host immune responses and promote viral production
Mitochondrial dynamics are pivotal for host immune responses upon infection, yet how viruses manipulate these processes to impair host defense and enhance viral fitness remain unclear. Here we show that Kaposi's sarcoma-associated herpesvirus (KSHV), an oncogenic virus also known as human herpesvirus 8, encodes Bcl-2 (vBcl-2), which reprograms mitochondrial architecture. It binds with NM23-H2, a host nucleoside diphosphate (NDP) kinase, to stimulate GTP-loading of the dynamin-related protein (DRP1) GTPase, which triggers mitochondrial fission, inhibits mitochondrial antiviral signaling protein (MAVS) aggregation and impairs interferon responses. An NM23-H2-binding-defective vBcl-2 mutant fails to evoke fission, leading to defective virion assembly due to activated MAVS-IFN signaling. Notably, we identify two key interferon-stimulated genes restricting vBcl-2-dependent virion morphogenesis. Using a high-throughput drug screening, we discover an inhibitor targeting vBcl-2-NM23-H2 interaction that blocks virion production in vitro. Our study identifies a mechanism in which KSHV manipulates mitochondrial dynamics to allow for virus assembly, and shows that targeting the virus-mitochondria interface represents a potential therapeutic strategy Overall design: RNAseq for empty vector, mutant E14A and WT vBcl-2 gene knock-in