Genome-wide CRISPR screens identify GATA6 as a proviral host factor for SARS-CoV-2 via modulation of ACE2

Ma’ayan Israeli, Yaara Finkel, Yfat Yahalom-Ronen, Nir Paran, Theodor Chitlaru, Ofir Israeli, Inbar Cohen-Gihon, Moshe Aftalion, Reut Falach, Shahar Rotem, Uri Elia, Ital Nemet, Limor Kliker, Michal Mandelboim, Adi Beth-Din, Tomer Israely, Ofer Cohen, Noam Stern-Ginossar and Adi Bercovich-Kinori ()
Additional contact information
Ma’ayan Israeli: Israel Institute for Biological Research
Yaara Finkel: Weizmann Institute of Science
Yfat Yahalom-Ronen: Israel Institute for Biological Research
Nir Paran: Israel Institute for Biological Research
Theodor Chitlaru: Israel Institute for Biological Research
Ofir Israeli: Israel Institute for Biological Research
Inbar Cohen-Gihon: Israel Institute for Biological Research
Moshe Aftalion: Israel Institute for Biological Research
Reut Falach: Israel Institute for Biological Research
Shahar Rotem: Israel Institute for Biological Research
Uri Elia: Israel Institute for Biological Research
Ital Nemet: Central Virology Laboratory, Public Health Services, Ministry of Health and Sheba Medical Center, Tel Hashomer
Limor Kliker: Central Virology Laboratory, Public Health Services, Ministry of Health and Sheba Medical Center, Tel Hashomer
Michal Mandelboim: Central Virology Laboratory, Public Health Services, Ministry of Health and Sheba Medical Center, Tel Hashomer
Adi Beth-Din: Israel Institute for Biological Research
Tomer Israely: Israel Institute for Biological Research
Ofer Cohen: Israel Institute for Biological Research
Noam Stern-Ginossar: Weizmann Institute of Science
Adi Bercovich-Kinori: Israel Institute for Biological Research

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract The global spread of SARS-CoV-2 led to major economic and health challenges worldwide. Revealing host genes essential for infection by multiple variants of SARS-CoV-2 can provide insights into the virus pathogenesis, and facilitate the development of novel therapeutics. Here, employing a genome-scale CRISPR screen, we provide a comprehensive data-set of cellular factors that are exploited by wild type SARS-CoV-2 as well as two additional recently emerged variants of concerns (VOCs), Alpha and Beta. We identified several host factors critical for SARS-CoV-2 infection, including various components belonging to the Clathrin-dependent transport pathway, ubiquitination, Heparan sulfate biogenesis and host phosphatidylglycerol biosynthesis. Comparative analysis of the different VOCs revealed the host factors KREMEN2 and SETDB1 as potential unique candidates required only to the Alpha variant. Furthermore, the analysis identified GATA6, a zinc finger transcription factor, as an essential proviral gene for all variants inspected. We show that GATA6 directly regulates ACE2 transcription and accordingly, is critical for SARS-CoV-2 cell entry. Analysis of clinical samples collected from SARS-CoV-2 infected individuals shows elevated levels of GATA6, suggesting a role in COVID-19 pathogenesis. Finally, pharmacological inhibition of GATA6 resulted in down-modulation of ACE2 and inhibition of viral infectivity. Overall, we show GATA6 may represent a target for the development of anti-SARS-CoV-2 therapeutic strategies and reaffirm the value of the CRISPR loss-of-function screens in providing a list of potential new targets for therapeutic interventions.

Date: 2022
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DOI: 10.1038/s41467-022-29896-z

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