A global map of the Zika virus phosphoproteome reveals host-driven regulation of viral particle release and cytopathogenicity
10 affiliations
- 1Department of Medicine, Division of Immunobiology, University of Vermont Larner College of Medicine, Burlington, Vermont, United States of America
- 2Cellular, Molecular, and Biomedical Sciences Graduate Program, University of Vermont, Burlington, Vermont, United States of America
- 3Department of Biology, University of Vermont, Burlington, Vermont, United States of America
- 4Department of Epidemiology, The University of North Carolina at Chapel Hill Gillings School of Global Public Health, Chapel Hill, North Carolina, United States of America
- 5Vermont Biomedical Research Network, University of Vermont, Burlington, Vermont, United States of America
- 6VLP Therapeutics, Inc., Gaithersburg, Maryland, United States of America
- 7MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, Scotland, United Kingdom
- 8Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, United States of America
- 9Department of Genetics, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, United States of America
- 10Department of Microbiology and Molecular Genetics, University of Vermont Larner College of Medicine, University of Vermont, Burlington, Vermont, United States of America
Abstract
Flaviviruses are enveloped, positive-strand RNA viruses that cause millions of infections in the human population annually. Although Zika virus (ZIKV) had been detected in humans as early as the 1950s, its reemergence in South America in 2015 resulted in a global health crisis. While flaviviruses encode 10 proteins that can be post-translationally modified by host enzymes, little is known regarding post-translational modifications (PTMs) of the flavivirus proteome. We used mass spectrometry to comprehensively identify host-driven PTMs on the ZIKV proteome. This approach allowed us to identify 43 PTMs across 8 ZIKV proteins, including several that are highly conserved within the Flavivirus genus. Notably, we found two phosphosites on the ZIKV envelope protein that are functionally important for viral propagation. Both appear to regulate viral particle release, while one also impacts ZIKV cytopathogenicity. Additionally, we discovered host kinases that interact with ZIKV proteins and determined that Bosutinib—an FDA-approved tyrosine kinase inhibitor that targets some of these host kinases—impairs ZIKV growth, in part by blocking phosphorylation of a tyrosine residue on the envelope protein. Thus, we have defined a high-resolution map of host-driven PTMs on ZIKV proteins as well as cellular interacting kinases, uncovered novel mechanisms of host driven-regulation of ZIKV particle release and cytopathogenicity, and identified an FDA-approved inhibitor of ZIKV growth. Author summary: Zika virus can cause neurological complications and birth defects in humans. The proteins made by viruses are the tools used to hijack human cells to repurpose them into virus production factories. We have a limited understanding of how the function(s) of these Zika virus proteins are regulated or the true range of functions each protein carries out. Herein, we created a comprehensive “map” of how human enzymes attach chemical tags—specifically phosphate and ubiquitin groups—to Zika virus proteins. These tags can act like molecular switches that can turn protein functions on or off. We discovered that two specific tagging sites on the virus’ outer shell protein, E, are critical for the efficient release of new virus particles from infected cells. Interestingly, blocking one of these tags also made the virus less harmful to cells, allowing the cells to survive longer. Furthermore, we identified an FDA-approved drug that successfully impairs virus growth, possibly by blocking these modifications. Our findings reveal new ways the virus controls its life cycle, a potentially novel role of the E protein for viral release, and suggest that repurposing drugs to target these host-driven processes could be a promising strategy for treating Zika virus infections.
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BibTeX
@article{manuelyan2026global,
title = {{A global map of the Zika virus phosphoproteome reveals host-driven regulation of viral particle release and cytopathogenicity}},
author = {Inessa Manuelyan and Anna M. Schmoker and Boyd L. Yount Jr. and Philip Eisenhauer and Judith I. Keller and Clarissa Gold and Dante Terino and Christopher M. Ziegler and Jeff Alexander and Edward Hutchinson and David Bhella and Christopher D. Syme and Douglas G. Widman and Mark T. Heise and Ralph S. Baric and Bryan A. Ballif and Jason W. Botten},
journal = {PLOS Pathogens},
year = {2026},
month = sep,
doi = {10.1371/journal.ppat.1014300},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014300},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A global map of the Zika virus phosphoproteome reveals host-driven regulation of viral particle release and cytopathogenicity
AU - Inessa Manuelyan
AU - Anna M. Schmoker
AU - Boyd L. Yount Jr.
AU - Philip Eisenhauer
AU - Judith I. Keller
AU - Clarissa Gold
AU - Dante Terino
AU - Christopher M. Ziegler
AU - Jeff Alexander
AU - Edward Hutchinson
AU - David Bhella
AU - Christopher D. Syme
AU - Douglas G. Widman
AU - Mark T. Heise
AU - Ralph S. Baric
AU - Bryan A. Ballif
AU - Jason W. Botten
PY - 2026
DA - 2026/09/03
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014300
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014300
AB - Flaviviruses are enveloped, positive-strand RNA viruses that cause millions of infections in the human population annually. Although Zika virus (ZIKV) had been detected in humans as early as the 1950s, its reemergence in South America in 2015 resulted in a global health crisis. While flaviviruses encode 10 proteins that can be post-translationally modified by host enzymes, little is known regarding post-translational modifications (PTMs) of the flavivirus proteome. We used mass spectrometry to comprehensively identify host-driven PTMs on the ZIKV proteome. This approach allowed us to identify 43 PTMs across 8 ZIKV proteins, including several that are highly conserved within the Flavivirus genus. Notably, we found two phosphosites on the ZIKV envelope protein that are functionally important for viral propagation. Both appear to regulate viral particle release, while one also impacts ZIKV cytopathogenicity. Additionally, we discovered host kinases that interact with ZIKV proteins and determined that Bosutinib—an FDA-approved tyrosine kinase inhibitor that targets some of these host kinases—impairs ZIKV growth, in part by blocking phosphorylation of a tyrosine residue on the envelope protein. Thus, we have defined a high-resolution map of host-driven PTMs on ZIKV proteins as well as cellular interacting kinases, uncovered novel mechanisms of host driven-regulation of ZIKV particle release and cytopathogenicity, and identified an FDA-approved inhibitor of ZIKV growth. Author summary: Zika virus can cause neurological complications and birth defects in humans. The proteins made by viruses are the tools used to hijack human cells to repurpose them into virus production factories. We have a limited understanding of how the function(s) of these Zika virus proteins are regulated or the true range of functions each protein carries out. Herein, we created a comprehensive “map” of how human enzymes attach chemical tags—specifically phosphate and ubiquitin groups—to Zika virus proteins. These tags can act like molecular switches that can turn protein functions on or off. We discovered that two specific tagging sites on the virus’ outer shell protein, E, are critical for the efficient release of new virus particles from infected cells. Interestingly, blocking one of these tags also made the virus less harmful to cells, allowing the cells to survive longer. Furthermore, we identified an FDA-approved drug that successfully impairs virus growth, possibly by blocking these modifications. Our findings reveal new ways the virus controls its life cycle, a potentially novel role of the E protein for viral release, and suggest that repurposing drugs to target these host-driven processes could be a promising strategy for treating Zika virus infections.
SN - 1553-7374
ER -