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

Abstract

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.

Hepatitis C Virus Dysregulates Polyamine and Proline Metabolism and Perturbs Urea Cycle

“…Polyamines also support replication of viruses by ensuring the hypusination of eIF5A. KSAV [47,50], Coxsackie virus B3 [67], vesicular stomatitis (VSV), influenza A, Zika and Chikungunya viruses [68] increase levels of hypusinated eIF5A. This factor enhances translation of the Ebola genome [69] and HIV transcription [70].…”

Hepatitis C Virus Dysregulates Polyamine and Proline Metabolism and Perturbs the Urea Cycle

“…Polyamines also support the replication of viruses by ensuring the hypusination of eIF5A. KSAV [ 51 , 54 ], Coxsackie virus B3 [ 71 ], vesicular stomatitis (VSV), influenza A, Zika, and Chikungunya viruses [ 72 ] increase levels of hypusinated eIF5A. This factor enhances the translation of the Ebola genome [ 73 ] and HIV transcription [ 74 ].…”