Pan-viral propagation blockade by inhibiting host cell PNPT1

Abstract

Successful viral propagation within infected cells necessitates the viruses' ability to overcome the cellular integrated stress response (ISR), triggered during viral infection, which in turn inhibits general protein translation. In our study, we unveil a shared tactic employed by viruses to suppress ISR by upregulating host cell polyribonucleotide nucleotidyltransferase 1 (PNPT1). The propagation of adenovirus, murine cytomegalovirus, and hepatovirus within their respective host cells induces PNPT1 expression. Notably, when PNPT1 is knocked down, the propagation of all three viruses is prevented. Mechanistically, the inhibition of PNPT1 facilitates the relocation of mitochondrial double-stranded RNAs (mt-dsRNAs) to the cytoplasm, where they activate RNA-activated protein kinase (PKR). This activation leads to eIF2α phosphorylation, resulting in the suppression of translation. Furthermore, by scrutinizing the PNPT1 recognition element and screening 17,728 FDA-approved drugs and bioactive compounds, we identify lanatoside C as a potent PNPT1 inhibitor. This compound robustly impedes the propagation of adenovirus, murine cytomegalovirus, and hepatovirus, along with suppressing the production of the SARS-CoV-2 spike protein. Our discoveries shed light on a novel strategy to impede pan-viral propagation by activating the host cell mt-dsRNA-PKR-eIF2α signaling axis.