Genome-scale CRISPR-Cas9 screen identifies host factors as potential therapeutic targets for SARS-CoV-2 infection

Madoka Sakai; Yoshie Masuda; Yusuke Tarumoto; Naoyuki Aihara; Yugo Tsunoda; Michiko Iwata; Yumiko Kamiya; Ryo Komorizono; Takeshi Noda; Kosuke Yusa; Keizo Tomonaga; Akiko Makino

doi:10.1016/j.isci.2024.110475

Genome-scale CRISPR-Cas9 screen identifies host factors as potential therapeutic targets for SARS-CoV-2 infection

iScience. 2024 Jul 8;27(8):110475. doi: 10.1016/j.isci.2024.110475. eCollection 2024 Aug 16.

Authors

Madoka Sakai¹, Yoshie Masuda², Yusuke Tarumoto², Naoyuki Aihara³, Yugo Tsunoda^{4

5

6}, Michiko Iwata¹, Yumiko Kamiya³, Ryo Komorizono¹, Takeshi Noda^{4

5

6}, Kosuke Yusa², Keizo Tomonaga^{1

7

8}, Akiko Makino^{1

7}

Affiliations

¹ Laboratory of RNA Viruses, Department of Virus Research, Institute for Life and Medical Sciences, Kyoto University, Kyoto 6068507, Japan.
² Laboratory of Stem Cell Genetics, Department of Biosystems Science, Institute for Life and Medical Sciences, Kyoto University, Kyoto 6068507, Japan.
³ Laboratory of Veterinary Pathology, Azabu University, Kanagawa 2520206, Japan.
⁴ Laboratory of Ultrastructural Virology, Department of Virus Research, Institute for Life and Medical Sciences, Kyoto University, Kyoto 6068507, Japan.
⁵ Laboratory of Ultrastructural Virology, Graduate School of Biostudies, Kyoto University, Kyoto 6068507, Japan.
⁶ CREST, Japan Science and Technology Agency, Saitama 1020076, Japan.
⁷ Laboratory of RNA Viruses, Department of Mammalian Regulatory Network, Graduate School of Biostudies, Kyoto University, Kyoto 6068507, Japan.
⁸ Department of Molecular Virology, Graduate School of Medicine, Kyoto University, Kyoto 6068507, Japan.

Abstract

Although many host factors important for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been reported, the mechanisms by which the virus interacts with host cells remain elusive. Here, we identified tripartite motif containing (TRIM) 28, TRIM33, euchromatic histone lysine methyltransferase (EHMT) 1, and EHMT2 as proviral factors involved in SARS-CoV-2 infection by CRISPR-Cas9 screening. Our result suggested that TRIM28 may play a role in viral particle formation and that TRIM33, EHMT1, and EHMT2 may be involved in viral transcription and replication. UNC0642, a compound that specifically inhibits the methyltransferase activity of EHMT1/2, strikingly suppressed SARS-CoV-2 growth in cultured cells and reduced disease severity in a hamster infection model. This study suggests that EHMT1/2 may be a therapeutic target for SARS-CoV-2 infection.

Keywords: Cell biology; Molecular biology; Virology.