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

Zhu, S.; Liu, Y.; Zhou, Z.; Zhang, Z.; Xiao, X.; Liu, Z.; Chen, A.; Dong, X.; Tian, F.; Chen, S.; Xu, Y.; Wang, C.; Li, Q.; Niu, X.; Pan, Q.; Du, S.; Xiao, J.; Wang, J.; Wei, W.

doi:10.1101/2021.04.08.438924

bioRxiv · 10.1101/2021.04.08.438924

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

Zhu, S.·Liu, Y.·Zhou, Z.·Zhang, Z.·Xiao, X.·Liu, Z.·Chen, A.·Dong, X.·Tian, F.·Chen, S.·Xu, Y.·Wang, C.·Li, Q.·Niu, X.·Pan, Q.·Du, S.·Xiao, J.·Wang, J.·Wei, W.

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Abstract

The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been endangering worldwide public health and economy. SARS-CoV-2 infects a variety of tissues where the known receptor ACE2 is low or almost absent, suggesting the existence of alternative pathways for virus entry. Here, we performed a genome-wide barcoded-CRISPRa screen to identify novel host factors that enable SARS-CoV-2 infection. In addition to 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 spikes N-terminal domain (NTD). Their essential and physiological roles have all been confirmed in either neuron or liver cells. In particular, LDLRAD3 and CLEC4G mediate SARS-CoV-2 entry and infection in a fashion independent of ACE2. 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 the therapeutic countermeasures against COVID-19.

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Zhu, S., Liu, Y., Zhou, Z., Zhang, Z., Xiao, X., Liu, Z., Chen, A., Dong, X., Tian, F., Chen, S., Xu, Y., Wang, C., Li, Q., Niu, X., Pan, Q., Du, S., Xiao, J., Wang, J., Wei, W.. 2021-04-09. Genome-wide CRISPR activation screen identifies novel receptors for SARS-CoV-2 entry. https://doi.org/10.1101/2021.04.08.438924

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