Journal
SCIENCE CHINA-LIFE SCIENCES
Volume 65, Issue 4, Pages 701-717Publisher
SCIENCE PRESS
DOI: 10.1007/s11427-021-1990-5
Keywords
CRISPRa screen; SARS-CoV-2; novel receptors
Categories
Funding
- National Key R&D Program of China [2020YFA0707800, 2020YFA0707600]
- Beijing Municipal Science & Technology Commission [Z181100001318009]
- National Natural Science Foundation of China [31930016, 31870893]
- Beijing Advanced Innovation Center for Genomics at Peking University
- Peking-Tsinghua Center for Life Sciences
- National Major Science & Technology Project for Control and Prevention of Major Infectious Diseases in China [2018ZX10301401]
- China Postdoctoral Science Foundation [2020M670031]
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The outbreak of COVID-19 caused by SARS-CoV-2 has led to a global health crisis. Through genome-wide screening, novel host factors (LDLRAD3, TMEM30A, and CLEC4G) have been identified as functional receptors for SARS-CoV-2, playing critical roles in infection.
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.
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