Polyamines and eIF5A hypusination facilitate SREBP2 translation and cholesterol synthesis to enhance 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 translation, the master transcriptional regulator of cholesterol synthesis genes. Measuring bulk transcription, we found polyamines support expression of cholesterol synthesis genes, regulated by SREBP2. 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.

Polyamine-Linked Cholesterol Incorporation in Rift Valley Fever Virus Particles Promotes Infectivity

“…The connection between polyamines and cholesterol synthesis has important implications for the effects of connected metabolic pathways on virus infection. Prior work showed that serum sterol levels were reduced in rats and mice treated with DFMO. , Our work, both here and in a previous one, demonstrates that polyamines support cholesterol synthesis through translation of SREBP2, a critical transcription factor for cholesterol biosynthetic genes. We previously showed that Coxsackievirus B3 attachment relied on both polyamines and the connected cholesterol synthetic pathway for infection.…”

“…We recently demonstrated that cellular polyamines promote cholesterol synthesis through polyamine-mediated SREBP2 translation and activity . We thus hypothesized that polyamine depletion via DFMO and subsequent cholesterol depletion would result in reduced RVFV replication.…”

“…We recently demonstrated that cellular polyamines promote cholesterol synthesis through polyamine-mediated SREBP2 translation and activity. 23 We thus hypothesized that polyamine depletion via DFMO and subsequent cholesterol depletion would result in reduced RVFV replication. If DFMO reduces cellular cholesterol, we considered that virions derived from these cells would have reduced cholesterol as well.…”

“…We recently found that polyamines facilitate cholesterol synthesis to impact enterovirus infection. 23 Here, we investigated the connections between polyamines and cholesterol synthesis in the context of bunyavirus infection using RVFV as our model system. We found that RVFV is sensitive to manipulations of cellular cholesterol, specifically at early stages in infection.…”

Persistent Coxsackievirus B3 Infection in Pancreatic Ductal Cells In Vitro Downregulates Cellular Polyamine Metabolism

“…Polyamines are critical molecules for both cellular functions ( 17 ) and CVB3 replication ( 14 , 18 , 19 ), and we hypothesized that persistent replication might be due to changes in polyamine metabolism, resulting in a detente between the virus and the host. Our observation of the emergence of mutant CVB3 (VP3 Q234R ), resistant to polyamine depletion, further highlighted this potential connection.…”