The role of furin cleavage site in SARS-CoV-2 spike protein-mediated membrane fusion in the presence or absence of trypsin
Shuai Xia, Qiaoshuai Lan, Shan Su, Xinling Wang, Wei Xu, Zezhong Liu, Yun Zhu, Qian Wang, Lu Lu & Shibo Jiang
Signal Transduction and Targeted Therapy volume 5, Article number: 92 (2020) Cite this article
The rapid spread of SARS-CoV-2 (also known as 2019-nCoV and HCoV-191), a novel lineage B betacoronavirus (βCoV), has caused a global pandemic of coronavirus disease (COVID-19). It has been speculated that RRAR, a unique furin-like cleavage site (FCS) in the spike protein (S), which is absent in other lineage B βCoVs, such as SARS-CoV, is responsible for its high infectivity and transmissibility.2
A coronavirus (CoV) infects the target cell by either cytoplasmic or endosomal membrane fusion. No matter what path it chooses, the final step of viral entry involves the release of RNA into the cytoplasm for replication. Therefore, the fusion capacity of the CoV-S is a leading indicator of infectivity of the corresponding virus. Consisting of S1 receptor-binding subunit and S2 fusion subunit, CoV-S needs to be primed through cleavage at S1/S2 site and S2′ site in order to mediate the membrane fusion (Fig. 1a). Previous studies have shown that an insertion of FCS consisting of multiple basic amino acids in the cleavage site of the haemagglutinin (HA) is associated with high virulence of influenza viruses.3 Coincidentally, phylogenetic analysis of SARS-CoV-2 identified an insertion of RRAR (FCS) at the S1/S2 site of SARS-CoV-2-S, which is absent in SARS-CoV and other SARS-related coronaviruses (SARSr-CoVs), particularly RaTG13, which has 96% identity of its genomic sequence to that of SARS-CoV-2 (Fig. 1b and Supplementary Fig. S1). Therefore, it has been speculated that this unique FCS may provide a gain-of-function, making SARS-CoV-2 easily enter into the host cell for infection, thus efficiently spreading throughout the human population, compared to other lineage B betacoronaviruses.2
