An integrated systems biology approach identifies the proteasome as a critical host machinery for ZIKV and DENV replication

Guang Song, Emily M. Lee, Jianbo Pan, Miao Xu, Hee Sool Rho, Yichen Cheng, Nadia Whitt, Shu Yang, Jennifer Kouznetsova, Carleen Klumpp-Thomas, Samuel G. Michael, Cedric Moore, Ki-Jun Yun, Kimberly M. Christian, Anton Simeonov, Wenwei Huang, Menghang Xia, Ruili Huang, Madhu Lal-Nag, Hengli TangWei Zheng, Jiang Qian, Hongjun Song, Guo Li Ming, Heng Zhu

Research output: Contribution to journalArticlepeer-review

Abstract

The Zika (ZIKV) and dengue (DENV) flaviviruses exhibit similar replicative processes but distinct clinical outcomes. A systematic understanding of virus-host protein-protein interaction networks can reveal cellular pathways critical to viral replication and disease pathogenesis. 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 to identify host proteins required for ZIKV infection uncovered proteasome proteins. Third, a high-throughput screening of 6,016 bioactive compounds for ZIKV inhibitors yielded 134 effective compounds, including six proteasome inhibitors that suppress both ZIKV and DENV replication. Integrative analyses of these orthogonal datasets pinpoints proteasome as critical host machinery for ZIKV/DENV replication. Our study provides multi-omics datasets for further studies of flavivirus-host interactions, disease pathogenesis, and new drug targets.

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - Mar 5 2020

Keywords

  • Chemical genetics screening
  • Protein-protein interaction
  • RNAi screening

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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