Comparative Flavivirus-Host Protein Interaction Mapping Reveals Mechanisms of Dengue and Zika Virus Pathogenesis

Priya S. Shah; Nichole Link; Gwendolyn M. Jang; Phillip P. Sharp; Tongtong Zhu; Danielle L. Swaney; Jeffrey R. Johnson; John Von Dollen; Holly R. Ramage; Laura Satkamp; Billy Newton; Ruth Hüttenhain; Marine J. Petit; Tierney Baum; Amanda Everitt; Orly Laufman; Michel Tassetto; Michael Shales; Erica Stevenson; Gabriel N. Iglesias; Leila Shokat; Shashank Tripathi; Vinod Balasubramaniam; Laurence G. Webb; Sebastian Aguirre; A. Jeremy Willsey; Adolfo Garcia-Sastre; Katherine S. Pollard; Sara Cherry; Andrea V. Gamarnik; Ivan Marazzi; Jack Taunton; Ana Fernandez-Sesma; Hugo J. Bellen; Raul Andino; Nevan J. Krogan

doi:10.1016/j.cell.2018.11.028

Comparative Flavivirus-Host Protein Interaction Mapping Reveals Mechanisms of Dengue and Zika Virus Pathogenesis

Priya S. Shah, Nichole Link, Gwendolyn M. Jang, Phillip P. Sharp, Tongtong Zhu, Danielle L. Swaney, Jeffrey R. Johnson, John Von Dollen, Holly R. Ramage, Laura Satkamp, Billy Newton, Ruth Hüttenhain, Marine J. Petit, Tierney Baum, Amanda Everitt, Orly Laufman, Michel Tassetto, Michael Shales, Erica Stevenson, Gabriel N. IglesiasLeila Shokat, Shashank Tripathi, Vinod Balasubramaniam, Laurence G. Webb, Sebastian Aguirre, A. Jeremy Willsey, Adolfo Garcia-Sastre, Katherine S. Pollard, Sara Cherry, Andrea V. Gamarnik, Ivan Marazzi, Jack Taunton, Ana Fernandez-Sesma, Hugo J. Bellen, Raul Andino, Nevan J. Krogan

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

190 Scopus citations

Abstract

Mosquito-borne flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV), are a growing public health concern. Systems-level analysis of how flaviviruses hijack cellular processes through virus-host protein-protein interactions (PPIs) provides information about their replication and pathogenic mechanisms. We used affinity purification-mass spectrometry (AP-MS) to compare flavivirus-host interactions for two viruses (DENV and ZIKV) in two hosts (human and mosquito). Conserved virus-host PPIs revealed that the flavivirus NS5 protein suppresses interferon stimulated genes by inhibiting recruitment of the transcription complex PAF1C and that chemical modulation of SEC61 inhibits DENV and ZIKV replication in human and mosquito cells. Finally, we identified a ZIKV-specific interaction between NS4A and ANKLE2, a gene linked to hereditary microcephaly, and showed that ZIKV NS4A causes microcephaly in Drosophila in an ANKLE2-dependent manner. Thus, comparative flavivirus-host PPI mapping provides biological insights and, when coupled with in vivo models, can be used to unravel pathogenic mechanisms. Comparing protein-protein interactions across dengue and Zika viruses reveals both common mechanisms and functionally distinct pathways contributing to infection outcomes.

Original language	English
Pages (from-to)	1931-1945.e18
Journal	Cell
Volume	175
Issue number	7
DOIs	https://doi.org/10.1016/j.cell.2018.11.028
State	Published - 13 Dec 2018

Keywords

ANKLE2
Drosophila
PAF1C
Sec61
Zika virus
dengue virus
endoplasmic reticulum
flavivirus
interferon stimulated genes
microcephaly
proteomics

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10.1016/j.cell.2018.11.028

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Shah, P. S., Link, N., Jang, G. M., Sharp, P. P., Zhu, T., Swaney, D. L., Johnson, J. R., Von Dollen, J., Ramage, H. R., Satkamp, L., Newton, B., Hüttenhain, R., Petit, M. J., Baum, T., Everitt, A., Laufman, O., Tassetto, M., Shales, M., Stevenson, E., ... Krogan, N. J. (2018). Comparative Flavivirus-Host Protein Interaction Mapping Reveals Mechanisms of Dengue and Zika Virus Pathogenesis. Cell, 175(7), 1931-1945.e18. https://doi.org/10.1016/j.cell.2018.11.028

@article{4399c7318e444622a738678961fa6f86,

title = "Comparative Flavivirus-Host Protein Interaction Mapping Reveals Mechanisms of Dengue and Zika Virus Pathogenesis",

abstract = "Mosquito-borne flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV), are a growing public health concern. Systems-level analysis of how flaviviruses hijack cellular processes through virus-host protein-protein interactions (PPIs) provides information about their replication and pathogenic mechanisms. We used affinity purification-mass spectrometry (AP-MS) to compare flavivirus-host interactions for two viruses (DENV and ZIKV) in two hosts (human and mosquito). Conserved virus-host PPIs revealed that the flavivirus NS5 protein suppresses interferon stimulated genes by inhibiting recruitment of the transcription complex PAF1C and that chemical modulation of SEC61 inhibits DENV and ZIKV replication in human and mosquito cells. Finally, we identified a ZIKV-specific interaction between NS4A and ANKLE2, a gene linked to hereditary microcephaly, and showed that ZIKV NS4A causes microcephaly in Drosophila in an ANKLE2-dependent manner. Thus, comparative flavivirus-host PPI mapping provides biological insights and, when coupled with in vivo models, can be used to unravel pathogenic mechanisms. Comparing protein-protein interactions across dengue and Zika viruses reveals both common mechanisms and functionally distinct pathways contributing to infection outcomes.",

keywords = "ANKLE2, Drosophila, PAF1C, Sec61, Zika virus, dengue virus, endoplasmic reticulum, flavivirus, interferon stimulated genes, microcephaly, proteomics",

author = "Shah, {Priya S.} and Nichole Link and Jang, {Gwendolyn M.} and Sharp, {Phillip P.} and Tongtong Zhu and Swaney, {Danielle L.} and Johnson, {Jeffrey R.} and {Von Dollen}, John and Ramage, {Holly R.} and Laura Satkamp and Billy Newton and Ruth H{\"u}ttenhain and Petit, {Marine J.} and Tierney Baum and Amanda Everitt and Orly Laufman and Michel Tassetto and Michael Shales and Erica Stevenson and Iglesias, {Gabriel N.} and Leila Shokat and Shashank Tripathi and Vinod Balasubramaniam and Webb, {Laurence G.} and Sebastian Aguirre and Willsey, {A. Jeremy} and Adolfo Garcia-Sastre and Pollard, {Katherine S.} and Sara Cherry and Gamarnik, {Andrea V.} and Ivan Marazzi and Jack Taunton and Ana Fernandez-Sesma and Bellen, {Hugo J.} and Raul Andino and Krogan, {Nevan J.}",

note = "Funding Information: We would like to thank Manon Eckhardt, Judd Hultquist, and Jacqueline Fabius for critical reading of the manuscript; the Krogan group for valuable comments; and Sima Lev, Michael Diamond, Chris Doe, Jim Skeath, BEI Resources, and the Bloomington Drosophila Stock Center for providing stocks, and reagents and the IDDRC Microscopy Core (NIH/NICHD U54HD083092). This work was supported by NIH/NIAID F32AI112262 to P.S.S., NIH/NINDS F32NS092270 to N.L., DOD/DARPA HR0011-11-C-0094 (PROPHECY) to R.A., A.V.G, A.F.S., and N.J.K., NIH/NIAID U19AI1186101 to A.F.S. and N.J.K., NIH/NIGMS P50 GM082250 to N.J.K., NIH/NIAID R01AI07345, R21AI116022 to A.F.S., UCSF Breast Cancer Research Funds to J.T., and NIH/NINDS U54NS093793, NIH/OD R24OD022005, and the Huffington Foundation to H.J.B. H.J.B. and N.L. are supported by HHMI. Funding Information: We would like to thank Manon Eckhardt, Judd Hultquist, and Jacqueline Fabius for critical reading of the manuscript; the Krogan group for valuable comments; and Sima Lev, Michael Diamond, Chris Doe, Jim Skeath, BEI Resources, and the Bloomington Drosophila Stock Center for providing stocks, and reagents and the IDDRC Microscopy Core ( NIH /NICHD U54HD083092). This work was supported by NIH /NIAID F32AI112262 to P.S.S., NIH /NINDS F32NS092270 to N.L., DOD /DARPA HR0011-11-C-0094 (PROPHECY) to R.A., A.V.G, A.F.S., and N.J.K., NIH /NIAID U19AI1186101 to A.F.S. and N.J.K., NIH /NIGMS P50 GM082250 to N.J.K., NIH /NIAID R01AI07345, R21AI116022 to A.F.S., UCSF Breast Cancer Research Funds to J.T., and NIH/NINDS U54NS093793 , NIH/OD R24OD022005 , and the Huffington Foundation to H.J.B. H.J.B. and N.L. are supported by HHMI. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2018",

month = dec,

day = "13",

doi = "10.1016/j.cell.2018.11.028",

language = "English",

volume = "175",

pages = "1931--1945.e18",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "7",

}

Shah, PS, Link, N, Jang, GM, Sharp, PP, Zhu, T, Swaney, DL, Johnson, JR, Von Dollen, J, Ramage, HR, Satkamp, L, Newton, B, Hüttenhain, R, Petit, MJ, Baum, T, Everitt, A, Laufman, O, Tassetto, M, Shales, M, Stevenson, E, Iglesias, GN, Shokat, L, Tripathi, S, Balasubramaniam, V, Webb, LG, Aguirre, S, Willsey, AJ, Garcia-Sastre, A, Pollard, KS, Cherry, S, Gamarnik, AV, Marazzi, I, Taunton, J, Fernandez-Sesma, A, Bellen, HJ, Andino, R & Krogan, NJ 2018, 'Comparative Flavivirus-Host Protein Interaction Mapping Reveals Mechanisms of Dengue and Zika Virus Pathogenesis', Cell, vol. 175, no. 7, pp. 1931-1945.e18. https://doi.org/10.1016/j.cell.2018.11.028

TY - JOUR

T1 - Comparative Flavivirus-Host Protein Interaction Mapping Reveals Mechanisms of Dengue and Zika Virus Pathogenesis

AU - Shah, Priya S.

AU - Link, Nichole

AU - Jang, Gwendolyn M.

AU - Sharp, Phillip P.

AU - Zhu, Tongtong

AU - Swaney, Danielle L.

AU - Johnson, Jeffrey R.

AU - Von Dollen, John

AU - Ramage, Holly R.

AU - Satkamp, Laura

AU - Newton, Billy

AU - Hüttenhain, Ruth

AU - Petit, Marine J.

AU - Baum, Tierney

AU - Everitt, Amanda

AU - Laufman, Orly

AU - Tassetto, Michel

AU - Shales, Michael

AU - Stevenson, Erica

AU - Iglesias, Gabriel N.

AU - Shokat, Leila

AU - Tripathi, Shashank

AU - Balasubramaniam, Vinod

AU - Webb, Laurence G.

AU - Aguirre, Sebastian

AU - Willsey, A. Jeremy

AU - Garcia-Sastre, Adolfo

AU - Pollard, Katherine S.

AU - Cherry, Sara

AU - Gamarnik, Andrea V.

AU - Marazzi, Ivan

AU - Taunton, Jack

AU - Fernandez-Sesma, Ana

AU - Bellen, Hugo J.

AU - Andino, Raul

AU - Krogan, Nevan J.

N1 - Funding Information: We would like to thank Manon Eckhardt, Judd Hultquist, and Jacqueline Fabius for critical reading of the manuscript; the Krogan group for valuable comments; and Sima Lev, Michael Diamond, Chris Doe, Jim Skeath, BEI Resources, and the Bloomington Drosophila Stock Center for providing stocks, and reagents and the IDDRC Microscopy Core (NIH/NICHD U54HD083092). This work was supported by NIH/NIAID F32AI112262 to P.S.S., NIH/NINDS F32NS092270 to N.L., DOD/DARPA HR0011-11-C-0094 (PROPHECY) to R.A., A.V.G, A.F.S., and N.J.K., NIH/NIAID U19AI1186101 to A.F.S. and N.J.K., NIH/NIGMS P50 GM082250 to N.J.K., NIH/NIAID R01AI07345, R21AI116022 to A.F.S., UCSF Breast Cancer Research Funds to J.T., and NIH/NINDS U54NS093793, NIH/OD R24OD022005, and the Huffington Foundation to H.J.B. H.J.B. and N.L. are supported by HHMI. Funding Information: We would like to thank Manon Eckhardt, Judd Hultquist, and Jacqueline Fabius for critical reading of the manuscript; the Krogan group for valuable comments; and Sima Lev, Michael Diamond, Chris Doe, Jim Skeath, BEI Resources, and the Bloomington Drosophila Stock Center for providing stocks, and reagents and the IDDRC Microscopy Core ( NIH /NICHD U54HD083092). This work was supported by NIH /NIAID F32AI112262 to P.S.S., NIH /NINDS F32NS092270 to N.L., DOD /DARPA HR0011-11-C-0094 (PROPHECY) to R.A., A.V.G, A.F.S., and N.J.K., NIH /NIAID U19AI1186101 to A.F.S. and N.J.K., NIH /NIGMS P50 GM082250 to N.J.K., NIH /NIAID R01AI07345, R21AI116022 to A.F.S., UCSF Breast Cancer Research Funds to J.T., and NIH/NINDS U54NS093793 , NIH/OD R24OD022005 , and the Huffington Foundation to H.J.B. H.J.B. and N.L. are supported by HHMI. Publisher Copyright: © 2018 Elsevier Inc.

PY - 2018/12/13

Y1 - 2018/12/13

N2 - Mosquito-borne flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV), are a growing public health concern. Systems-level analysis of how flaviviruses hijack cellular processes through virus-host protein-protein interactions (PPIs) provides information about their replication and pathogenic mechanisms. We used affinity purification-mass spectrometry (AP-MS) to compare flavivirus-host interactions for two viruses (DENV and ZIKV) in two hosts (human and mosquito). Conserved virus-host PPIs revealed that the flavivirus NS5 protein suppresses interferon stimulated genes by inhibiting recruitment of the transcription complex PAF1C and that chemical modulation of SEC61 inhibits DENV and ZIKV replication in human and mosquito cells. Finally, we identified a ZIKV-specific interaction between NS4A and ANKLE2, a gene linked to hereditary microcephaly, and showed that ZIKV NS4A causes microcephaly in Drosophila in an ANKLE2-dependent manner. Thus, comparative flavivirus-host PPI mapping provides biological insights and, when coupled with in vivo models, can be used to unravel pathogenic mechanisms. Comparing protein-protein interactions across dengue and Zika viruses reveals both common mechanisms and functionally distinct pathways contributing to infection outcomes.

AB - Mosquito-borne flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV), are a growing public health concern. Systems-level analysis of how flaviviruses hijack cellular processes through virus-host protein-protein interactions (PPIs) provides information about their replication and pathogenic mechanisms. We used affinity purification-mass spectrometry (AP-MS) to compare flavivirus-host interactions for two viruses (DENV and ZIKV) in two hosts (human and mosquito). Conserved virus-host PPIs revealed that the flavivirus NS5 protein suppresses interferon stimulated genes by inhibiting recruitment of the transcription complex PAF1C and that chemical modulation of SEC61 inhibits DENV and ZIKV replication in human and mosquito cells. Finally, we identified a ZIKV-specific interaction between NS4A and ANKLE2, a gene linked to hereditary microcephaly, and showed that ZIKV NS4A causes microcephaly in Drosophila in an ANKLE2-dependent manner. Thus, comparative flavivirus-host PPI mapping provides biological insights and, when coupled with in vivo models, can be used to unravel pathogenic mechanisms. Comparing protein-protein interactions across dengue and Zika viruses reveals both common mechanisms and functionally distinct pathways contributing to infection outcomes.

KW - ANKLE2

KW - Drosophila

KW - PAF1C

KW - Sec61

KW - Zika virus

KW - dengue virus

KW - endoplasmic reticulum

KW - flavivirus

KW - interferon stimulated genes

KW - microcephaly

KW - proteomics

UR - http://www.scopus.com/inward/record.url?scp=85057612645&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2018.11.028

DO - 10.1016/j.cell.2018.11.028

M3 - Article

C2 - 30550790

AN - SCOPUS:85057612645

SN - 0092-8674

VL - 175

SP - 1931-1945.e18

JO - Cell

JF - Cell

IS - 7

ER -

Comparative Flavivirus-Host Protein Interaction Mapping Reveals Mechanisms of Dengue and Zika Virus Pathogenesis

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Keywords

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