Identification of picornavirus proteins that inhibit de novo nucleotide synthesis during infection
Publication date
2025-07-03
Authors
Nouwen, Lonneke V
Zaal, Esther A
Buitendijk, Inge
Zwaagstra, Marleen
Aloise, Chiara
van Vliet, Arno L W
Schipper, Jelle G
van Mil, Alain
Berkers, Celia R
van Kuppeveld, Frank J M
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Abstract
Viruses, including picornaviruses, modulate cellular metabolism to generate sufficient building blocks for virus replication and dissemination. Previously, we showed that two picornaviruses, coxsackievirus B3 (CVB3) and EMCV, remodel nucleotide metabolism during infection. Here, we investigated whether this modulation is attributable to specific viral proteins. For this, we studied the modulation of metabolism by several recombinant CVB3 and EMCV viruses in HeLa cells. Using isotope tracing metabolomics with three distinct labels, 13C6-glucose or 13C5/15N2-glutamine, we reveal that the 2A protease of CVB3 and the Leader protein of EMCV inhibit de novo nucleotide synthesis. Furthermore, we show that nucleotide metabolism is also reprogrammed by CVB3 and EMCV in human induced pluripotent stem cell-derived cardiomyocytes. Our insights are important to increase understanding of picornavirus-host interactions and may lead to novel therapeutic strategies.
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Nouwen, L V, Zaal, E A, Buitendijk, I, Zwaagstra, M, Aloise, C, van Vliet, A L W, Schipper, J G, van Mil, A, Berkers, C R & van Kuppeveld, F J M 2025, 'Identification of picornavirus proteins that inhibit de novo nucleotide synthesis during infection', PLoS pathogens, vol. 21, no. 7 July, e1013293. https://doi.org/10.1371/journal.ppat.1013293