%0 Journal Article
%T Sequential glycosylations at the multibasic cleavage site of SARS-CoV-2 spike protein regulate viral activity.
%A Wang S
%A Ran W
%A Sun L
%A Fan Q
%A Zhao Y
%A Wang B
%A Yang J
%A He Y
%A Wu Y
%A Wang Y
%A Chen L
%A Chuchuay A
%A You Y
%A Zhu X
%A Wang X
%A Chen Y
%A Wang Y
%A Chen YQ
%A Yuan Y
%A Zhao J
%A Mao Y
%J Nat Commun
%V 15
%N 1
%D 2024 May 16
%M 38755139
%F 17.694
%R 10.1038/s41467-024-48503-x
%X 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.