An Integrated Systems Biology Approach Identifies the Proteasome as A Critical Host Machinery for ZIKV and DENV Replication |
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| Authors: | Guang Song Emily MLee Jianbo Pan Miao Xu Hee-Sool Rho Yichen Cheng Nadia Whitt Shu Yang Jennifer Kouznetsova Carleen Klumpp-Thomas Samuel GMichael Cedric Moore Ki-Jun Yoon Kimberly MChristian Anton Simeonov Wenwei Huang Menghang Xia Ruili Huang Madhu Lal-Nag Hengli Tang Wei Zheng Jiang Qian Hongjun Song Guo-li Ming Heng Zhu |
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| Institution: | 1. Department of Pharmacology & Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA;2. Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA;3. Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA;4. National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA;5. Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China;6. Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA;7. Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA;8. Department of Cell and Developmental Biology, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA;9. Institute for Regenerative Medicine, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA;10. The Epigenetics Institute, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA |
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| Abstract: | The Zika virus (ZIKV) and dengue virus (DENV) flaviviruses exhibit similar replicative processes but have distinct clinical outcomes. A systematic understanding of virus–host protein–pro-tein interaction networks can reveal cellular pathways critical to viral replication and disease patho-genesis. Here we employed three independent systems biology approaches toward this goal. First, protein array analysis of direct interactions between individual ZIKV/DENV viral proteins and 20,240 human proteins revealed multiple conserved cellular pathways and protein complexes, including proteasome complexes. Second, an RNAi screen of 10,415 druggable genes identified the host proteins required for ZIKV infection and uncovered that proteasome proteins were crucial in this process. Third, high-throughput screening of 6016 bioactive compounds for ZIKV inhibition yielded 134 effective compounds, including six proteasome inhibitors that suppress both ZIKV and DENV replication. Integrative analyses of these orthogonal datasets pinpoint proteasomes as crit-ical host machinery for ZIKV/DENV replication. Our study provides multi-omics datasets for fur-ther studies of flavivirus–host interactions, disease pathogenesis, and new drug targets. |
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| Keywords: | Protein–protein interaction RNAi screening Chemical genetics screening Multi-omics |
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