Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-21213-4
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Funding
- National Key Research and Development Program of China [2020YFA0707701]
- National Natural Science Foundation of China [32041005]
- Project of Novel Coronavirus Research of Fudan University
- Development Programs for COVID-19 of Shanghai Science and Technology Commission [20431900401]
- Natural Science Foundation of Shanghai [19ZR1470400]
- Natural Science Foundation of Guangdong Province [202020012611500005]
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The SARS-CoV-2 spike protein contains a multi-basic cleavage site that affects virus entry and transmission, as shown in hamster models. Host factors affecting virus entry were identified through a genome-wide CRISPR screen.
The global spread of SARS-CoV-2 is posing major public health challenges. One feature of SARS-CoV-2 spike protein is the insertion of multi-basic residues at the S1/S2 subunit cleavage site. Here, we find that the virus with intact spike (Sfull) preferentially enters cells via fusion at the plasma membrane, whereas a clone (Sdel) with deletion disrupting the multi-basic S1/S2 site utilizes an endosomal entry pathway. Using Sdel as model, we perform a genome-wide CRISPR screen and identify several endosomal entry-specific regulators. Experimental validation of hits from the CRISPR screen shows that host factors regulating the surface expression of angiotensin-converting enzyme 2 (ACE2) affect entry of Sfull virus. Animal-to-animal transmission with the Sdel virus is reduced compared to Sfull in the hamster model. These findings highlight the critical role of the S1/S2 boundary of SARS-CoV-2 spike protein in modulating virus entry and transmission and provide insights into entry of coronaviruses. The SARS-CoV-2 spike protein contains a multi-basic cleavage site. Here, the authors show how this multi-basic cleavage site affects entry of SARS-CoV-2 into cells and transmission in the hamster model and identify host factors affecting entry of SARS-CoV-2 in a genome-wide CRISPR screen.
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