Zika virus remodelled ER membranes contain proviral factors involved in redox and methylation pathways

Solène Denolly, Alexey Stukalov, Uladzimir Barayeu, Alina N. Rosinski, Paraskevi Kritsiligkou, Sebastian Joecks, Tobias P. Dick, Andreas Pichlmair and Ralf Bartenschlager ()
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Solène Denolly: Heidelberg University, Medical Faculty Heidelberg, Department of Infectious Diseases, Molecular Virology, Center for Integrative Infectious Disease Research
Alexey Stukalov: Technical University of Munich, School of Medicine, Institute of Virology
Uladzimir Barayeu: DKFZ-ZMBH Alliance
Alina N. Rosinski: Heidelberg University, Medical Faculty Heidelberg, Department of Infectious Diseases, Molecular Virology, Center for Integrative Infectious Disease Research
Paraskevi Kritsiligkou: DKFZ-ZMBH Alliance
Sebastian Joecks: Heidelberg University, Medical Faculty Heidelberg, Department of Infectious Diseases, Molecular Virology, Center for Integrative Infectious Disease Research
Tobias P. Dick: DKFZ-ZMBH Alliance
Andreas Pichlmair: Technical University of Munich, School of Medicine, Institute of Virology
Ralf Bartenschlager: Heidelberg University, Medical Faculty Heidelberg, Department of Infectious Diseases, Molecular Virology, Center for Integrative Infectious Disease Research

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract Zika virus (ZIKV) has emerged as a global health issue, yet neither antiviral therapy nor a vaccine are available. ZIKV is an enveloped RNA virus, replicating in the cytoplasm in close association with ER membranes. Here, we isolate ER membranes from ZIKV-infected cells and determine their proteome. Forty-six host cell factors are enriched in ZIKV remodeled membranes, several of these having a role in redox and methylation pathways. Four proteins are characterized in detail: thioredoxin reductase 1 (TXNRD1) contributing to folding of disulfide bond containing proteins and modulating ZIKV secretion; aldo-keto reductase family 1 member C3 (AKR1C3), regulating capsid protein abundance and thus, ZIKV assembly; biliverdin reductase B (BLVRB) involved in ZIKV induced lipid peroxidation and increasing stability of viral transmembrane proteins; adenosylhomocysteinase (AHCY) indirectly promoting m6A methylation of ZIKV RNA by decreasing the level of S- adenosyl homocysteine and thus, immune evasion. These results highlight the involvement of redox and methylation enzymes in the ZIKV life cycle and their accumulation at virally remodeled ER membranes.

Date: 2023
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DOI: 10.1038/s41467-023-43665-6

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