Abstract
The SARS-CoV-2 coronavirus responsible for the global pandemic contains a novel furin cleavage site in the spike protein (S) that increases viral infectivity and syncytia formation in cells. Here, we show that O-glycosylation near the furin cleavage site is mediated by members of the GALNT enzyme family, resulting in decreased furin cleavage and decreased syncytia formation. Moreover, we show that O-glycosylation is dependent on the novel proline at position 681 (P681). Mutations of P681 seen in the highly transmissible alpha and delta variants abrogate O-glycosylation, increase furin cleavage, and increase syncytia formation. Finally, we show that GALNT family members capable of glycosylating S are expressed in human respiratory cells that are targets for SARS-CoV-2 infection. Our results suggest that host O-glycosylation may influence viral infectivity/tropism by modulating furin cleavage of S and provide mechanistic insight into the role of the P681 mutations found in the highly transmissible alpha and delta variants.
Highlights
The novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which is responsible for the current coronavirus disease 2019 (COVID-19) pandemic, contains a unique insertion of four amino acids (PRRA) at the S1/S2 boundary of the spike protein (S) that is not present in SARS-CoV and other related coronaviruses [1] (Fig. 1A)
This furin cleavage site is unique to SARS-CoV-2 and has been shown to increase pseudoviral infectivity and syncytia formation in cell culture [2,3,4,5], suggesting that it may play a role in viral transmission and disease progression in vivo
Our results demonstrate that O-glycosylation decreases furin cleavage of S and decreases syncytia formation in cells, raising the possibility that differences in GalNAc:polypeptide N-acetylgalactosaminyltransferases (GALNTs) expression from individual to individual could influence viral transmission in vivo
Summary
The novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which is responsible for the current coronavirus disease 2019 (COVID-19) pandemic, contains a unique insertion of four amino acids (PRRA) at the S1/S2 boundary of the spike protein (S) that is not present in SARS-CoV and other related coronaviruses [1] (Fig. 1A). The S protein present in the viral envelope is responsible for binding to host cells and mediating viral entry into cells after S undergoes a number of cleavages This PRRA insertion generates a furin cleavage site that has been shown to increase pseudoviral infectivity, tropism, and syncytia formation in cell culture [2,3,4,5] (Fig. 1A). The recent emergence of highly transmissible SARS-CoV-2 variants (alpha or B.1.1.7, and delta or B.1.617.2), which contain mutations in the novel proline (P681) that lies near the sites of O-glycosylation and furin cleavage, has further highlighted the need to understand how changes in this region potentially influence viral infectivity [11, 12]. Our results further suggest that individual variation in the expression of certain GALNTs in respiratory cells (and the extent of S glycosylation) may influence viral transmission
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