HCMV US30 induces TMED10-DRP1-mediated mitochondrial fission and apoptosis to promote viral multiplication

Human cytomegalovirus (HCMV) hijacks host components to modulate cell death for its optimized replication and dissemination. We identified HCMV US30 as a viral factor that induces caspase-dependent apoptosis. US30 induces both DRP1-dependent mitochondrial fission and subsequent apoptosis, as well as IRE1α-mediated unfolded protein responses (UPR). Mechanistically, US30 interacts with NPL4 to impair ER-associated protein degradation and subsequently induce UPR. In parallel, US30 associates with the Endoplasmic reticulum-Golgi intermediate compartment (ERGIC) protein TMED10 and promotes its translocation to the cytoplasm, where it activates DRP1 to initiate mitochondrial fission and subsequent caspase-dependent apoptosis. US30 induces UPR and mitochondrial fission/apoptosis via distinct domains, and the two distinct effects are uncoupled. We also show that US30-induced mitochondrial fission and apoptosis, but not UPR, contribute to the multiplication and dissemination of HCMV. These findings reveal that HCMV US30 induces mitochondrial fission and apoptosis to promote viral replication and dissemination and provide potential targets for intervention of HCMV-induced diseases.IMPORTANCEHuman cytomegalovirus (HCMV) is a human pathogenic herpesvirus that causes global epidemics. HCMV hijacks cellular compartments to maintain its replication and dissemination, which is associated with host cell fate. Here, we identified HCMV US30 as a viral factor to induce caspase-dependent apoptosis. Proteomics analysis revealed that US30 disrupts both ER and mitochondrial homeostasis. We further found that US30-induced mitochondrial fission, but not UPR, mediates apoptosis. Mechanistically, our results indicate that US30 interacts with NPL4 to activate UPR and associates with TMED10 to trigger mitochondrial fission, which are dependent on distinct domains of US30. Most importantly, we found that US30 alters the localization of TMED10 from ERGIC to the cytosol to activate DRP1. Finally, our results showed that US30-induced mitochondrial fission and apoptosis, but not UPR, contribute to the multiplication and dissemination of HCMV. These findings enhance our understanding of HCMV-host interplay and provide potential targets for intervention of HCMV-induced diseases.