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Receptome profiling identifies KREMEN1 and ASGR1 as alternative functional receptors of SARS-CoV-2

查看全文 作　　者：Yunqing [1]Gu;Jun [1,2]Cao;Xinyu [1]Zhang;Hai [1,3]Gao;Yuyan [4]Wang;Jia [5]Wang;Juan [6]He;Xiaoyi [1]Jiang;Jinlan [1]Zhang;Guanghui [2]Shen;Jie [1]Yang;Xichen [1,2]Zheng;Gaowei [4]Hu;Yuanfei [4]Zhu;Shujuan [4]Du;Yunkai [4]Zhu;Rong [4]Zhang;Jianqing [1,7]Xu;Fei [1]Lan;Di [4]Qu;Guoliang [1,5]Xu;Yun [5,6]Zhao;Dong [6]Gao;Youhua [1,4]Xie;Min [1,2]Luo;Zhigang [1]Lu 高影响力作者 机构地区：[1]The 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,Shanghai Institute of Infectious Diseases and Biosecurity,Shanghai Medical College,Fudan University,Shanghai,China;[2]Institute of Pediatrics,Children’s Hospital of Fudan University,Shanghai,China;[3]Zhongshan-Xuhui Hospital,Fudan University,Shanghai,China;[4]Key Laboratory of Medical Molecular Virology(MOE/MOH),School of Basic Medical Sciences,Shanghai Institute of Infectious Diseases and Biosecurity,Shanghai Medical College,Fudan University,Shanghai,China;[5]State 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,China;[6]State Key Laboratory of Cell Biology,Shanghai Key Laboratory of Molecular Andrology,CAS Center for Excellence in Molecular Cell Science,Institute of Biochemistry and Cell Biology,Shanghai Institutes for Biological Sciences,Chinese Academy of Sciences,Shanghai,China;[7]Shanghai Public Health Clinical Center,Fudan University,Shanghai,China高影响力机构 出　　处：《Cell Research》索引2022年第32卷第1期,共14页高影响力期刊 基　　金：funded by the National Natural Science Foundation of China(81873438,81873922,81971921,81830054 and 81772723,32125013);the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16020905);the Basic Frontier Science Research Program of Chinese Academy of Sciences(No.ZDBS-LY-SM015);the National Key R&D Program of China(2020YFA0509002 and 2017YFA0505500);the National Key Project for Infectious Diseases of China(2018ZX10301208 and 2018ZX10302207-004-002). 摘　　要：Host cellular receptors play key roles in the determination of virus tropism and pathogenesis.However,little is known about SARS-CoV-2 host receptors with the exception of ACE2.Furthermore,ACE2 alone cannot explain the multi-organ tropism of SARS-CoV-2 nor the clinical differences between SARS-CoV-2 and SARS-CoV,suggesting the involvement of other receptor(s).Here,we performed genomic receptor profiling to screen 5054 human membrane proteins individually for interaction with the SARS-CoV-2 capsid spike(S)protein.Twelve proteins,including ACE2,ASGR1,and KREMEN1,were identified with diverse S-binding affinities and patterns.ASGR1 or KREMEN1 is sufficient for the entry of SARS-CoV-2 but not SARS-CoV in vitro and in vivo.SARS-CoV-2 utilizes distinct ACE2/ASGR1/KREMEN1(ASK)receptor combinations to enter different cell types,and the expression of ASK together displays a markedly stronger correlation with virus susceptibility than that of any individual receptor at both the cell and tissue levels.The cocktail of ASK-related neutralizing antibodies provides the most substantial blockage of SARS-CoV-2 infection in human lung organoids when compared to individual antibodies.Our study revealed an interacting host receptome of SARS-CoV-2,and identified ASGR1 and KREMEN1 as alternative functional receptors that play essential roles in ACE2-independent virus entry,providing insight into SARS-CoV-2 tropism and pathogenesis,as well as a community resource and potential therapeutic strategies for further COVID-19 investigations. 关 键 词：markedly INVOLVEMENT FUNCTIONAL
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