A comprehensive Drosophila resource to identify key functional interactions between SARS-CoV-2 factors and host proteins

• Published in: Cell reports (Cambridge) 2023-08, Vol.42 (8), p.112842-112842, Article 112842
• Main Authors: Guichard, Annabel, Lu, Shenzhao, Kanca, Oguz, Bressan, Daniel, Huang, Yan, Ma, Mengqi, Sanz Juste, Sara, Andrews, Jonathan C., Jay, Kristy L., Sneider, Marketta, Schwartz, Ruth, Huang, Mei-Chu, Bei, Danqing, Pan, Hongling, Ma, Liwen, Lin, Wen-Wen, Auradkar, Ankush, Bhagwat, Pranjali, Park, Soo, Wan, Kenneth H., Ohsako, Takashi, Takano-Shimizu, Toshiyuki, Celniker, Susan E., Wangler, Michael F., Yamamoto, Shinya, Bellen, Hugo J., Bier, Ethan
• Format: Article
• Language: English
• Subjects: Actins; Animals; Animals, Genetically Modified; arginylation; ATE1; COVID-19; CP: Microbiology; DRC; Drosophila; Drosophila Covid-19 resource; human interactors; Humans; non-structural proteins; NSP8; NSPs; Orf3a; SARS-CoV-2; SARS-CoV-2 - genetics
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112842

Development of effective therapies against SARS-CoV-2 infections relies on mechanistic knowledge of virus-host interface. Abundant physical interactions between viral and host proteins have been identified, but few have been functionally characterized. Harnessing the power of fly genetics, we develop a comprehensive Drosophila COVID-19 resource (DCR) consisting of publicly available strains for conditional tissue-specific expression of all SARS-CoV-2 encoded proteins, UAS-human cDNA transgenic lines encoding established host-viral interacting factors, and GAL4 insertion lines disrupting fly homologs of SARS-CoV-2 human interacting proteins. We demonstrate the utility of the DCR to functionally assess SARS-CoV-2 genes and candidate human binding partners. We show that NSP8 engages in strong genetic interactions with several human candidates, most prominently with the ATE1 arginyltransferase to induce actin arginylation and cytoskeletal disorganization, and that two ATE1 inhibitors can reverse NSP8 phenotypes. The DCR enables parallel global-scale functional analysis of SARS-CoV-2 components in a prime genetic model system. [Display omitted] •A Drosophila resource enables functional analysis of all SARS-Cov2 factors•This collection allows expression of viral factors and human binding partners•It also includes GAL4 insertions mutating fly orthologs of host binding partners•NSP8 interacts with other viral factors and with the ATE1 arginyltransferase Guichard et al. develop Drosophila tools for conditional tissue-specific expression of individual SARS-CoV-2 factors and candidate human binding partners, as well as functional characterization of their fly orthologs. This resource is shared with the scientific community to promote analysis of in vivo interactions between viral and host factors.