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

Cell research 2022 Jan

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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. © 2021. The Author(s), under exclusive licence to Center for Excellence in Molecular Cell Science, CAS.

Citation

Yunqing Gu, Jun Cao, Xinyu Zhang, Hai Gao, Yuyan Wang, Jia Wang, Juan He, Xiaoyi Jiang, Jinlan Zhang, Guanghui Shen, Jie Yang, Xichen Zheng, Gaowei Hu, Yuanfei Zhu, Shujuan Du, Yunkai Zhu, Rong Zhang, Jianqing Xu, Fei Lan, Di Qu, Guoliang Xu, Yun Zhao, Dong Gao, Youhua Xie, Min Luo, Zhigang Lu. Receptome profiling identifies KREMEN1 and ASGR1 as alternative functional receptors of SARS-CoV-2. Cell research. 2022 Jan;32(1):24-37