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Interaction network of SARS-CoV-2 with host receptome through spike protein

Yunqing Gu, Jun Cao, Xinyu Zhang, Hai Gao, Yuyan Wang, Jia Wang, Jinlan Zhang, Guanghui Shen, Xiaoyi Jiang, Jie Yang, Xichen Zheng, Jianqing Xu, Cheng Cheng Zhang, Fei Lan, Di Qu, Yun Zhao, Guoliang Xu, Youhua Xie, Min Luo, Zhigang Lu
doi: https://doi.org/10.1101/2020.09.09.287508
Yunqing Gu
1The Fifth People’s Hospital of Shanghai, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
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Jun Cao
1The Fifth People’s Hospital of Shanghai, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
2Institute of Pediatrics of Children’s Hospital of Fudan University, Shanghai 201102, China
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Xinyu Zhang
1The Fifth People’s Hospital of Shanghai, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
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Hai Gao
1The Fifth People’s Hospital of Shanghai, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
3Zhongshan-Xuhui Hospital, Fudan Univeristy, Shanghai 200020, China
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Yuyan Wang
4Key Laboratory of Medical Molecular Virology (MOE/MOH), School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
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Jia Wang
5State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
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Jinlan Zhang
1The Fifth People’s Hospital of Shanghai, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
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Guanghui Shen
2Institute of Pediatrics of Children’s Hospital of Fudan University, Shanghai 201102, China
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Xiaoyi Jiang
1The Fifth People’s Hospital of Shanghai, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
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Jie Yang
1The Fifth People’s Hospital of Shanghai, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
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Xichen Zheng
1The Fifth People’s Hospital of Shanghai, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
2Institute of Pediatrics of Children’s Hospital of Fudan University, Shanghai 201102, China
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Jianqing Xu
1The Fifth People’s Hospital of Shanghai, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
6Shanghai Public Health Clinical Center, Fudan University, Shanghai 200433, China
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Cheng Cheng Zhang
7Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
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Fei Lan
1The Fifth People’s Hospital of Shanghai, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
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Di Qu
4Key Laboratory of Medical Molecular Virology (MOE/MOH), School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
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Yun Zhao
5State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
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Guoliang Xu
1The Fifth People’s Hospital of Shanghai, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
5State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
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Youhua Xie
1The Fifth People’s Hospital of Shanghai, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
4Key Laboratory of Medical Molecular Virology (MOE/MOH), School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
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  • For correspondence: zhiganglu@fudan.edu.cn luo_min@fudan.edu.cn yhxie@fudan.edu.cn
Min Luo
1The Fifth People’s Hospital of Shanghai, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
2Institute of Pediatrics of Children’s Hospital of Fudan University, Shanghai 201102, China
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  • For correspondence: zhiganglu@fudan.edu.cn luo_min@fudan.edu.cn yhxie@fudan.edu.cn
Zhigang Lu
1The Fifth People’s Hospital of Shanghai, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
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  • For correspondence: zhiganglu@fudan.edu.cn luo_min@fudan.edu.cn yhxie@fudan.edu.cn
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SUMMARY

Host cellular receptors are key determinants of virus tropism and pathogenesis. Virus utilizes multiple receptors for attachment, entry, or specific host responses. However, other than ACE2, little is known about SARS-CoV-2 receptors. Furthermore, ACE2 cannot easily interpret the multi-organ tropisms of SARS-CoV-2 nor the clinical differences between SARS-CoV-2 and SARS-CoV. To identify host cell receptors involved in SARS-CoV-2 interactions, we performed genomic receptor profiling to screen almost all human membrane proteins, with SARS-CoV-2 capsid spike (S) protein as the target. Twelve receptors were identified, including ACE2. Most receptors bind at least two domains on S protein, the receptor-binding-domain (RBD) and the N-terminal-domain (NTD), suggesting both are critical for virus-host interaction. Ectopic expression of ASGR1 or KREMEN1 is sufficient to enable entry of SARS-CoV-2, but not SARS-CoV and MERS-CoV. Analyzing single-cell transcriptome profiles from COVID-19 patients revealed that virus susceptibility in airway epithelial ciliated and secretory cells and immune macrophages highly correlates with expression of ACE2, KREMEN1 and ASGR1 respectively, and ACE2/ASGR1/KREMEN1 (ASK) together displayed a much better correlation than any individual receptor. Based on modeling of systemic SARS-CoV-2 host interactions through S receptors, we revealed ASK correlation with SARS-CoV-2 multi-organ tropism and provided potential explanations for various COVID-19 symptoms. Our study identified a panel of SARS-CoV-2 receptors with diverse binding properties, biological functions, and clinical correlations or implications, including ASGR1 and KREMEN1 as the alternative entry receptors, providing insights into critical interactions of SARS-CoV-2 with host, as well as a useful resource and potential drug targets for COVID-19 investigation.

Competing Interest Statement

M.L., Z.L., Y.Z. H.G. and Y.X. are listed as inventors on a pending patent application for the newly identified S receptors described in this manuscript. The other authors declare no competing interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted September 13, 2020.
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Interaction network of SARS-CoV-2 with host receptome through spike protein
Yunqing Gu, Jun Cao, Xinyu Zhang, Hai Gao, Yuyan Wang, Jia Wang, Jinlan Zhang, Guanghui Shen, Xiaoyi Jiang, Jie Yang, Xichen Zheng, Jianqing Xu, Cheng Cheng Zhang, Fei Lan, Di Qu, Yun Zhao, Guoliang Xu, Youhua Xie, Min Luo, Zhigang Lu
bioRxiv 2020.09.09.287508; doi: https://doi.org/10.1101/2020.09.09.287508
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Interaction network of SARS-CoV-2 with host receptome through spike protein
Yunqing Gu, Jun Cao, Xinyu Zhang, Hai Gao, Yuyan Wang, Jia Wang, Jinlan Zhang, Guanghui Shen, Xiaoyi Jiang, Jie Yang, Xichen Zheng, Jianqing Xu, Cheng Cheng Zhang, Fei Lan, Di Qu, Yun Zhao, Guoliang Xu, Youhua Xie, Min Luo, Zhigang Lu
bioRxiv 2020.09.09.287508; doi: https://doi.org/10.1101/2020.09.09.287508

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