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Genome-wide CRISPR activation screen identifies candidate receptors for SARS-CoV-2 entry

Science China(Life Sciences) 2022年第4期65卷 701-717页

作者： Shiyou Zhu Ying Liu Zhuo Zhou Zhiying Zhang Xia Xiao Zhiheng Liu Ang Chen Xiaojing Dong Feng Tian Shihua Chen Yiyuan Xu Chunhui Wang Qiheng Li Xuran Niu Qian Pan Shuo Du Junyu Xiao Jianwei Wang Wensheng Wei Biomedical Pioneering Innovation Center Beijing Advanced Innovation Center for GenomicsPeking-Tsinghua Center for Life SciencesPeking University Genome Editing Research CenterState Key Laboratory of Protein and Plant Gene ResearchSchool of Life SciencesPeking UniversityBeijing100871China State Key Laboratory of Protein and Plant Gene Research School of Life SciencesPeking UniversityPeking-Tsinghua Center for Life SciencesPeking UniversityBeijing Advanced Innovation Center for GenomicsPeking UniversityBeijing 100871China NHC Key Laboratory of Systems Biology of Pathogens and Christophe Merieux Laboratory Institute of Pathogen BiologyChinese Academy of Medical Sciences and Peking Union Medical CollegeKey Laboratory of Respiratory Disease PathogenomicsChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China Academy for Advanced Interdisciplinary Studies Peking UniversityBeijing 100871China

The outbreak of coronavirus disease 2019(COVID-19) caused by SARS-CoV-2 has created a global health crisis. SARS-CoV-2 infects varieties of tissues where the known receptor ACE2 is low or almost absent, suggesting the existence of alternative viral entry pathways. Here, we performed a genome-wide barcoded-CRISPRa screen to identify novel host factors that enable SARS-CoV-2 infection. Beyond known host proteins, i.e., ACE2, TMPRSS2, and NRP1, we identified multiple host components,among which LDLRAD3, TMEM30A, and CLEC4G were confirmed as functional receptors for SARS-CoV-2. All these membrane proteins bind directly to spike’s N-terminal domain(NTD). Their essential and physiological roles have been confirmed in either neuron or liver cells. In particular, LDLRAD3 and CLEC4G mediate SARS-CoV-2 entry and infection in an ACE2-independent fashion. The identification of the novel receptors and entry mechanisms could advance our understanding of the multiorgan tropism of SARS-CoV-2, and may shed light on the development of COVID-19 countermeasures.

关键词： CRISPRa screen SARS-CoV-2 novel receptors

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