A global lipid map defines a network essential for Zika virus replication

Hans C. Leier; Jules B. Weinstein; Jennifer E. Kyle; Joon Yong Lee; Lisa M. Bramer; Kelly G. Stratton; Douglas Kempthorne; Aaron R. Navratil; Endale G. Tafesse; Thorsten Hornemann; William B. Messer; Edward A. Dennis; Thomas O. Metz; Eric Barklis; Fikadu G. Tafesse

doi:10.1038/s41467-020-17433-9

A global lipid map defines a network essential for Zika virus replication

Hans C. Leier, Jules B. Weinstein, Jennifer E. Kyle, Joon Yong Lee, Lisa M. Bramer, Kelly G. Stratton, Douglas Kempthorne, Aaron R. Navratil, Endale G. Tafesse, Thorsten Hornemann, William B. Messer, Edward A. Dennis, Thomas O. Metz, Eric Barklis, Fikadu G. Tafesse

Molecular Microbiology and Immunology

Research output: Contribution to journal › Article › peer-review

43 Scopus citations

Abstract

Zika virus (ZIKV), an arbovirus of global concern, remodels intracellular membranes to form replication sites. How ZIKV dysregulates lipid networks to allow this, and consequences for disease, is poorly understood. Here, we perform comprehensive lipidomics to create a lipid network map during ZIKV infection. We find that ZIKV significantly alters host lipid composition, with the most striking changes seen within subclasses of sphingolipids. Ectopic expression of ZIKV NS4B protein results in similar changes, demonstrating a role for NS4B in modulating sphingolipid pathways. Disruption of sphingolipid biosynthesis in various cell types, including human neural progenitor cells, blocks ZIKV infection. Additionally, the sphingolipid ceramide redistributes to ZIKV replication sites, and increasing ceramide levels by multiple pathways sensitizes cells to ZIKV infection. Thus, we identify a sphingolipid metabolic network with a critical role in ZIKV replication and show that ceramide flux is a key mediator of ZIKV infection.

Original language	English (US)
Article number	3652
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-17433-9
State	Published - Dec 1 2020

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Leier, H. C., Weinstein, J. B., Kyle, J. E., Lee, J. Y., Bramer, L. M., Stratton, K. G., Kempthorne, D., Navratil, A. R., Tafesse, E. G., Hornemann, T., Messer, W. B., Dennis, E. A., Metz, T. O., Barklis, E., & Tafesse, F. G. (2020). A global lipid map defines a network essential for Zika virus replication. Nature communications, 11(1), Article 3652. https://doi.org/10.1038/s41467-020-17433-9

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abstract = "Zika virus (ZIKV), an arbovirus of global concern, remodels intracellular membranes to form replication sites. How ZIKV dysregulates lipid networks to allow this, and consequences for disease, is poorly understood. Here, we perform comprehensive lipidomics to create a lipid network map during ZIKV infection. We find that ZIKV significantly alters host lipid composition, with the most striking changes seen within subclasses of sphingolipids. Ectopic expression of ZIKV NS4B protein results in similar changes, demonstrating a role for NS4B in modulating sphingolipid pathways. Disruption of sphingolipid biosynthesis in various cell types, including human neural progenitor cells, blocks ZIKV infection. Additionally, the sphingolipid ceramide redistributes to ZIKV replication sites, and increasing ceramide levels by multiple pathways sensitizes cells to ZIKV infection. Thus, we identify a sphingolipid metabolic network with a critical role in ZIKV replication and show that ceramide flux is a key mediator of ZIKV infection.",

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AU - Bramer, Lisa M.

AU - Stratton, Kelly G.

AU - Kempthorne, Douglas

AU - Navratil, Aaron R.

AU - Tafesse, Endale G.

AU - Hornemann, Thorsten

AU - Messer, William B.

AU - Dennis, Edward A.

AU - Metz, Thomas O.

AU - Barklis, Eric

AU - Tafesse, Fikadu G.

PY - 2020/12/1

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N2 - Zika virus (ZIKV), an arbovirus of global concern, remodels intracellular membranes to form replication sites. How ZIKV dysregulates lipid networks to allow this, and consequences for disease, is poorly understood. Here, we perform comprehensive lipidomics to create a lipid network map during ZIKV infection. We find that ZIKV significantly alters host lipid composition, with the most striking changes seen within subclasses of sphingolipids. Ectopic expression of ZIKV NS4B protein results in similar changes, demonstrating a role for NS4B in modulating sphingolipid pathways. Disruption of sphingolipid biosynthesis in various cell types, including human neural progenitor cells, blocks ZIKV infection. Additionally, the sphingolipid ceramide redistributes to ZIKV replication sites, and increasing ceramide levels by multiple pathways sensitizes cells to ZIKV infection. Thus, we identify a sphingolipid metabolic network with a critical role in ZIKV replication and show that ceramide flux is a key mediator of ZIKV infection.

AB - Zika virus (ZIKV), an arbovirus of global concern, remodels intracellular membranes to form replication sites. How ZIKV dysregulates lipid networks to allow this, and consequences for disease, is poorly understood. Here, we perform comprehensive lipidomics to create a lipid network map during ZIKV infection. We find that ZIKV significantly alters host lipid composition, with the most striking changes seen within subclasses of sphingolipids. Ectopic expression of ZIKV NS4B protein results in similar changes, demonstrating a role for NS4B in modulating sphingolipid pathways. Disruption of sphingolipid biosynthesis in various cell types, including human neural progenitor cells, blocks ZIKV infection. Additionally, the sphingolipid ceramide redistributes to ZIKV replication sites, and increasing ceramide levels by multiple pathways sensitizes cells to ZIKV infection. Thus, we identify a sphingolipid metabolic network with a critical role in ZIKV replication and show that ceramide flux is a key mediator of ZIKV infection.

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A global lipid map defines a network essential for Zika virus replication

Abstract

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