| Popis: |
Metabolism is key to cellular processes that ultimately underly the ability of a virus to productively infect a cell. Polyamines are small metabolites that are vital for many host cell processes including cellular proliferation, transcription, and translation, and these molecules are also key in virus infection. Depletion of polyamines inhibits viral infection via diverse mechanisms, including by inhibiting polymerase activity, cellular attachment, and translation of viral proteins. The precise mechanisms underlying many of these phenotypes remain to be understood. We have shown previously that Coxsackievirus B3 requires polyamines for attachment and protease function; however, the mechanism behind this is unknown. Here, we report that polyamines9 involvement in translation, through a process called hypusination, globally affects expression of cholesterol synthesis genes by supporting SREBP2 translation, the master transcriptional regulator of cholesterol synthesis genes. By measuring bulk cellular transcription, we found that polyamines enhance the expression of a wide variety of cholesterol synthesis genes, ultimately regulated by SREBP2. The net effect of polyamine depletion on cells negatively impacts CVB3 attachment and replication in polyamine depleted cells by depleting cellular cholesterol. Exogenous cholesterol rescues CVB3 binding and replication, and mutant CVB3 resistant to polyamine depletion exhibits resistance to cholesterol perturbation. This study provides a novel link between polyamine synthesis and cholesterol homeostasis that explains data seen in animals and provides a mechanism through which polyamines impact CVB3 infection. |
