Polyamines and eIF5A hypusination facilitate SREBP2 synthesis and cholesterol production leading to enhanced enterovirus attachment and infection

Author summaryViruses rely on cellular metabolism for productive infection. How viruses interact with and manipulate metabolism impacts viral replication and pathogenesis. Metabolic pathways are frequently interconnected, and perturbation of one pathway can have wide-ranging impacts on other metabolites within the cell. Here, we show that polyamines, small positively-charged metabolites critical to virus infection, regulate cholesterol synthesis, which ultimately impacts viral attachment. We find that polyamines' role in translation is critical to their regulation of cholesterol synthesis. These data have important implications for the connections between polyamine and sterol synthesis as well as how these molecules impact virus replication. Metabolism is key to cellular processes that underlie the ability of a virus to productively infect. Polyamines are small metabolites vital for many host cell processes including proliferation, transcription, and translation. Polyamine depletion also inhibits virus infection via diverse mechanisms, including inhibiting polymerase activity and viral translation. We showed that Coxsackievirus B3 (CVB3) attachment requires polyamines; however, the mechanism was unknown. Here, we report polyamines' involvement in translation, through a process called hypusination, promotes expression of cholesterol synthesis genes by supporting SREBP2 synthesis, the master transcriptional regulator of cholesterol synthesis genes. Measuring bulk transcription, we find polyamines support expression of cholesterol synthesis genes, regulated by SREBP2. Thus, polyamine depletion inhibits CVB3 by depleting cellular cholesterol. Exogenous cholesterol rescues CVB3 attachment, and mutant CVB3 resistant to polyamine depletion exhibits resistance to cholesterol perturbation. This study provides a novel link between polyamine and cholesterol homeostasis, a mechanism through which polyamines impact CVB3 infection.

Automated summary

Viruses rely on cellular metabolism for infection, and it has been discovered that polyamines regulate cholesterol synthesis, which affects viral attachment. The role of polyamines in translation is crucial for their regulation of cholesterol synthesis.