Interferon-induced transmembrane proteins block Zika virus infection and prevent a non-apoptotic, paraptosis-like cell death pathway

We report that ZIKV induces massive vacuolization followed by “ implosive ” cell death in human epithelial cells, primary skin fibroblasts and astrocytes, a phenomenon which is exacerbated when IFITM3 levels are low. It is reminiscent of paraptosis, a caspase-independent, non-apoptotic form of cell death associated with the formation of large cytoplasmic vacuoles. We further show that ZIKV-induced vacuoles are derived from the endoplasmic reticulum (ER) and dependent on the PI3K/Akt signaling axis. Inhibiting the Sec61 ER translocon in ZIKV-infected cells blocked vacuole formation and viral production. Our results provide mechanistic insight behind the ZIKV-induced cytopathic effect and indicate that IFITM3, by acting as a gatekeeper for incoming virus, restricts virus takeover of the ER and subsequent cell death. Future directions include determining whether additional antiviral functions of IFITM3, such as the reduction of HIV-1 virion fusogenicity, also manifest during flavivirus infections. Alex Compton received his Ph.D. in Molecular and Cellular Biology from the University of Washington in 2012. As a doctoral student in the laboratory of Dr. Michael Emerman (Fred Hutchinson Cancer Research Center), he investigated the HIV-1 Vif protein and its target APOBEC3G, revealing lentivirus-driven evolution of host proteins on a million-year time scale. Dr. Compton was the recipient of a Pasteur Foundation Postdoctoral Fellowship and an ANRS (French National Agency on AIDS Re...
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