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

© 2022. The Author(s)..

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.

Medienart:

E-Artikel

Erscheinungsjahr:

2022

Erschienen:

2022

Enthalten in:

Zur Gesamtaufnahme - volume:13

Enthalten in:

Nature communications - 13(2022), 1 vom: 25. Apr., Seite 2237

Sprache:

Englisch

Beteiligte Personen:

Israeli, Ma'ayan [VerfasserIn]
Finkel, Yaara [VerfasserIn]
Yahalom-Ronen, Yfat [VerfasserIn]
Paran, Nir [VerfasserIn]
Chitlaru, Theodor [VerfasserIn]
Israeli, Ofir [VerfasserIn]
Cohen-Gihon, Inbar [VerfasserIn]
Aftalion, Moshe [VerfasserIn]
Falach, Reut [VerfasserIn]
Rotem, Shahar [VerfasserIn]
Elia, Uri [VerfasserIn]
Nemet, Ital [VerfasserIn]
Kliker, Limor [VerfasserIn]
Mandelboim, Michal [VerfasserIn]
Beth-Din, Adi [VerfasserIn]
Israely, Tomer [VerfasserIn]
Cohen, Ofer [VerfasserIn]
Stern-Ginossar, Noam [VerfasserIn]
Bercovich-Kinori, Adi [VerfasserIn]

Links:

Volltext

Themen:

Angiotensin-Converting Enzyme 2
EC 3.4.15.1
EC 3.4.17.23
GATA6 Transcription Factor
GATA6 protein, human
Journal Article
Peptidyl-Dipeptidase A

Anmerkungen:

Date Completed 27.04.2022

Date Revised 16.09.2023

published: Electronic

Citation Status MEDLINE

doi:

10.1038/s41467-022-29896-z

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM339980958