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Coxsackievirus B3 Responds to Polyamine Depletion via Enhancement of 2A and 3C Protease Activity

1
Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA
2
Infectious Disease and Immunology Research Institute, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA
*
Author to whom correspondence should be addressed.
Viruses 2019, 11(5), 403; https://doi.org/10.3390/v11050403
Received: 9 April 2019 / Revised: 26 April 2019 / Accepted: 26 April 2019 / Published: 30 April 2019
(This article belongs to the Section Animal Viruses)
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Abstract

Polyamines are small positively-charged molecules abundant in eukaryotic cells that are crucial to RNA virus replication. In eukaryotic cells, polyamines facilitate processes such as transcription, translation, and DNA replication, and viruses similarly rely on polyamines to facilitate transcription and translation. Whether polyamines function at additional stages in viral replication remains poorly understood. Picornaviruses, including Coxsackievirus B3 (CVB3), are sensitive to polyamine depletion both in vitro and in vivo; however, precisely how polyamine function in picornavirus infection has not been described. Here, we describe CVB3 mutants that arise with passage in polyamine-depleted conditions. We observe mutations in the 2A and 3C proteases, and we find that these mutant proteases confer resistance to polyamine depletion. Using a split luciferase reporter system to measure protease activity, we determined that polyamines facilitate viral protease activity. We further observe that the 2A and 3C protease mutations enhance reporter protease activity in polyamine-depleted conditions. Finally, we find that these mutations promote cleavage of cellular eIF4G during infection of polyamine-depleted cells. In sum, our results suggest that polyamines are crucial to protease function during picornavirus infection. Further, these data highlight viral proteases as potential antiviral targets and highlight how CVB3 may overcome polyamine-depleting antiviral therapies. View Full-Text
Keywords: polyamines; Coxsackievirus B3; protease polyamines; Coxsackievirus B3; protease
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Dial, C.N.; Tate, P.M.; Kicmal, T.M.; Mounce, B.C. Coxsackievirus B3 Responds to Polyamine Depletion via Enhancement of 2A and 3C Protease Activity. Viruses 2019, 11, 403.

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