{Reference Type}: Journal Article
{Title}: Sequential glycosylations at the multibasic cleavage site of SARS-CoV-2 spike protein regulate viral activity.
{Author}: Wang S;Ran W;Sun L;Fan Q;Zhao Y;Wang B;Yang J;He Y;Wu Y;Wang Y;Chen L;Chuchuay A;You Y;Zhu X;Wang X;Chen Y;Wang Y;Chen YQ;Yuan Y;Zhao J;Mao Y;
{Journal}: Nat Commun
{Volume}: 15
{Issue}: 1
{Year}: 2024 May 16
{Factor}: 17.694
{DOI}: 10.1038/s41467-024-48503-x
{Abstract}: The multibasic furin cleavage site at the S1/S2 boundary of the spike protein is a hallmark of SARS-CoV-2 and plays a crucial role in viral infection. However, the mechanism underlying furin activation and its regulation remain poorly understood. Here, we show that GalNAc-T3 and T7 jointly initiate clustered O-glycosylations in the furin cleavage site of the SARS-CoV-2 spike protein, which inhibit furin processing, suppress the incorporation of the spike protein into virus-like-particles and affect viral infection. Mechanistic analysis reveals that the assembly of the spike protein into virus-like particles relies on interactions between the furin-cleaved spike protein and the membrane protein of SARS-CoV-2, suggesting a possible mechanism for furin activation. Interestingly, mutations in the spike protein of the alpha and delta variants of the virus confer resistance against glycosylation by GalNAc-T3 and T7. In the omicron variant, additional mutations reverse this resistance, making the spike protein susceptible to glycosylation in vitro and sensitive to GalNAc-T3 and T7 expression in human lung cells. Our findings highlight the role of glycosylation as a defense mechanism employed by host cells against SARS-CoV-2 and shed light on the evolutionary interplay between the host and the virus.