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

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

Author information

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

PMID:
30550790
PMCID:
PMC6474419
[Available on 2019-12-13]
DOI:
10.1016/j.cell.2018.11.028

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