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. 2021 Aug 20;65(4):701–717. doi: 10.1007/s11427-021-1990-5

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

Shiyou Zhu 1,#, Ying Liu 1,#, Zhuo Zhou 1,#, Zhiying Zhang 2,3,4,#, Xia Xiao 5,6, Zhiheng Liu 1, Ang Chen 1,7, Xiaojing Dong 5,6, Feng Tian 1, Shihua Chen 2,3,4,7, Yiyuan Xu 1, Chunhui Wang 1, Qiheng Li 1, Xuran Niu 1, Qian Pan 1, Shuo Du 2,3,4, Junyu Xiao 2,3,4,✉, Jianwei Wang 5,6,✉, Wensheng Wei 1,✉
PMCID: PMC8384091  PMID: 34431042

Abstract

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.

Supporting Information

The supporting information is available online at 10.1007/s11427-021-1990-5. The supporting materials are published as submitted, without typesetting or editing. The responsibility for scientific accuracy and content remains entirely with the authors.

Keywords: CRISPRa screen, SARS-CoV-2, novel receptors

Electronic Supplementary Material

11427_2021_1990_MOESM1_ESM.xlsx (4.3MB, xlsx)

Supplementary material, approximately 4.28 MB.

11427_2021_1990_MOESM2_ESM.xlsx (747.6KB, xlsx)

Supplementary material, approximately 748 KB.

11427_2021_1990_MOESM3_ESM.xlsx (28.4KB, xlsx)

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11427_2021_1990_MOESM4_ESM.xlsx (9.6KB, xlsx)

Supplementary material, approximately 12 KB.

11427_2021_1990_MOESM5_ESM.xlsx (9.9KB, xlsx)

Supplementary material, approximately 12 KB.

11427_2021_1990_MOESM6_ESM.pdf (1.5MB, pdf)

Supplementary material, approximately 1.48 MB.

Acknowledgements

We acknowledge the National Center for Protein Sciences (Beijing) at Peking University for their assistance with fluorescence-activated cell sorting and SPR measurements, particularly Dr. Jia Luo, Ms Huan Yang, Ms Liying Du and Ms Hui Li for their technical help. We acknowledge Dr. Ying Yu (Peking University) for her assistance in preparing the NGS library. This project was supported by funds from the National Key R&D Program of China (2020YFA0707800 to W.W., 2020YFA0707600 to Z.Z.), Beijing Municipal Science & Technology Commission (Z181100001318009), the National Natural Science Foundation of China (31930016), Beijing Advanced Innovation Center for Genomics at Peking University and the Peking-Tsinghua Center for Life Sciences (to W. W.), the National Natural Science Foundation of China (31870893), the National Major Science & Technology Project for Control and Prevention of Major Infectious Diseases in China (2018ZX10301401 to Z.Z.), and China Postdoctoral Science Foundation (2020M670031 to Y.L.).

Footnotes

Compliance and ethics

The author(s) declare that they have no conflict of interest.

Contributed equally to this work

Contributor Information

Junyu Xiao, Email: junyuxiao@pku.edu.cn.

Jianwei Wang, Email: wangjw28@163.com.

Wensheng Wei, Email: wswei@pku.edu.cn.

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Supplementary Materials

11427_2021_1990_MOESM1_ESM.xlsx (4.3MB, xlsx)

Supplementary material, approximately 4.28 MB.

11427_2021_1990_MOESM2_ESM.xlsx (747.6KB, xlsx)

Supplementary material, approximately 748 KB.

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Supplementary material, approximately 32 KB.

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Supplementary material, approximately 12 KB.

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11427_2021_1990_MOESM6_ESM.pdf (1.5MB, pdf)

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