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

Annabel Guichard; Shenzhao Lu; Oguz Kanca; Daniel Bressan; Yan Huang; Mengqi Ma; Sara Sanz Juste; Jonathan C Andrews; Kristy L Jay; Marketta Sneider; Ruth Schwartz; Mei-Chu Huang; Danqing Bei; Hongling Pan; Liwen Ma; Wen-Wen Lin; Ankush Auradkar; Pranjali Bhagwat; Soo Park; Kenneth H Wan; Takashi Ohsako; Toshiyuki Takano-Shimizu; Susan E Celniker; Michael F Wangler; Shinya Yamamoto; Hugo J Bellen; Ethan Bier

doi:10.1016/j.celrep.2023.112842

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

Cell Rep. 2023 Aug 29;42(8):112842. doi: 10.1016/j.celrep.2023.112842. Epub 2023 Jul 20.

Authors

Annabel Guichard¹, Shenzhao Lu², Oguz Kanca², Daniel Bressan³, Yan Huang², Mengqi Ma², Sara Sanz Juste⁴, Jonathan C Andrews², Kristy L Jay², Marketta Sneider¹, Ruth Schwartz¹, Mei-Chu Huang², Danqing Bei², Hongling Pan², Liwen Ma², Wen-Wen Lin², Ankush Auradkar¹, Pranjali Bhagwat², Soo Park⁵, Kenneth H Wan⁵, Takashi Ohsako⁶, Toshiyuki Takano-Shimizu⁷, Susan E Celniker⁵, Michael F Wangler⁸, Shinya Yamamoto⁹, Hugo J Bellen¹⁰, Ethan Bier¹¹

Affiliations

¹ Section of Cell and Developmental Biology, University of California, San Diego (UCSD), La Jolla, CA 92093, USA.
² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
³ Section of Cell and Developmental Biology, University of California, San Diego (UCSD), La Jolla, CA 92093, USA; Instituto de Ciências Biomédicas (ICB), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
⁴ Section of Cell and Developmental Biology, University of California, San Diego (UCSD), La Jolla, CA 92093, USA; Department of Epigenetics & Molecular Carcinogenesis at MD Anderson, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Center for Cancer Epigenetics, MD Anderson Cancer Center, Houston, TX, USA.
⁵ Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
⁶ Advanced Technology Center, Kyoto Institute of Technology, Kyoto 606-8585, Japan.
⁷ Kyoto Drosophila Stock Center and Faculty of Applied Biology, Kyoto Institute of Technology, Kyoto 616-8354, Japan.
⁸ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
⁹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Development, Disease Models & Therapeutics Graduate Program, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: yamamoto@bcm.edu.
¹⁰ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: hbellen@bcm.edu.
¹¹ Section of Cell and Developmental Biology, University of California, San Diego (UCSD), La Jolla, CA 92093, USA; Tata Institute for Genetics and Society - UCSD, La Jolla, CA 92093, USA. Electronic address: ebier@ucsd.edu.

Abstract

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.

Keywords: ATE1; CP: Microbiology; DRC; Drosophila; Drosophila Covid-19 resource; NSP8; NSPs; Orf3a; SARS-CoV-2; arginylation; human interactors; non-structural proteins.

Publication types

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

MeSH terms

Actins
Animals
Animals, Genetically Modified
COVID-19*
Drosophila
Humans
SARS-CoV-2* / genetics

Substances

Actins

Abstract

Publication types

MeSH terms

Substances

Grants and funding