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

Cell. 2018 Dec 13;175(7):1931-1945.e18. doi: 10.1016/j.cell.2018.11.028.

Authors

Priya S Shah¹, Nichole Link², Gwendolyn M Jang³, Phillip P Sharp⁴, Tongtong Zhu⁵, Danielle L Swaney³, Jeffrey R Johnson³, John Von Dollen³, Holly R Ramage⁶, Laura Satkamp³, Billy Newton³, Ruth Hüttenhain³, Marine J Petit⁷, Tierney Baum⁸, Amanda Everitt⁸, Orly Laufman⁹, Michel Tassetto⁹, Michael Shales³, Erica Stevenson³, Gabriel N Iglesias¹⁰, Leila Shokat³, Shashank Tripathi¹¹, Vinod Balasubramaniam¹², Laurence G Webb⁵, Sebastian Aguirre¹¹, A Jeremy Willsey¹³, Adolfo Garcia-Sastre¹⁴, Katherine S Pollard¹⁵, Sara Cherry⁶, Andrea V Gamarnik¹⁰, Ivan Marazzi¹⁶, Jack Taunton¹⁷, Ana Fernandez-Sesma¹⁸, Hugo J Bellen¹⁹, Raul Andino²⁰, Nevan J Krogan²¹

Affiliations

¹ Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA; Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA; The J. David Gladstone Institutes, San Francisco, CA, USA.
² Department of Molecular and Human Genetics, and Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute, Houston, TX, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX, USA.
³ Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA; The J. David Gladstone Institutes, San Francisco, CA, USA.
⁴ Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.
⁵ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶ Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA.
⁷ Department of Chemical Engineering, Department of Microbiology and Molecular Genetics, University of California Davis, Davis, CA, USA.
⁸ Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
⁹ Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA.
¹⁰ Fundación Instituto Leloir-CONICET, Buenos Aires, Argentina.
¹¹ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹² Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Selangor, Malaysia.
¹³ Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA; Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA; Department of Psychiatry, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
¹⁴ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁵ Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA; The J. David Gladstone Institutes, San Francisco, CA, USA; Department of Epidemiology and Biostatistics, Institute for Human Genetics, and Institute for Computational Health Sciences, University of California San Francisco, San Francisco, CA, USA; Chan-Zuckerberg Biohub, San Francisco, CA, USA.
¹⁶ Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁷ Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA.
¹⁸ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁹ Department of Molecular and Human Genetics, and Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute, Houston, TX, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX, USA. Electronic address: hbellen@bcm.edu.
²⁰ Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA. Electronic address: raul.andino@ucsf.edu.
²¹ Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA; The J. David Gladstone Institutes, San Francisco, CA, USA. Electronic address: nevan.krogan@ucsf.edu.

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.

Keywords: ANKLE2; Drosophila; PAF1C; Sec61; Zika virus; dengue virus; endoplasmic reticulum; flavivirus; interferon stimulated genes; microcephaly; proteomics.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Cell Line, Tumor
Culicidae
Dengue Virus* / genetics
Dengue Virus* / metabolism
Dengue Virus* / pathogenicity
Dengue* / genetics
Dengue* / metabolism
Dengue* / pathology
HEK293 Cells
Humans
Membrane Proteins* / genetics
Membrane Proteins* / metabolism
Nuclear Proteins* / genetics
Nuclear Proteins* / metabolism
Protein Interaction Mapping
Viral Nonstructural Proteins* / genetics
Viral Nonstructural Proteins* / metabolism
Zika Virus Infection* / genetics
Zika Virus Infection* / metabolism
Zika Virus Infection* / pathology
Zika Virus* / genetics
Zika Virus* / metabolism
Zika Virus* / pathogenicity

Substances

ANKLE2 protein, human
Membrane Proteins
NS4A protein, Dengue virus
NS5 protein, dengue virus
Nuclear Proteins
Viral Nonstructural Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding