tetano
Editor, Senior Moderator
Nat Commun
. 2024 May 16;15(1):4162.
doi: 10.1038/s41467-024-48503-x. Sequential glycosylations at the multibasic cleavage site of SARS-CoV-2 spike protein regulate viral activity
Shengjun Wang[SUP] #[/SUP][SUP] 1 2 [/SUP], Wei Ran[SUP] #[/SUP][SUP] 3 [/SUP], Lingyu Sun[SUP] #[/SUP][SUP] 1 [/SUP], Qingchi Fan[SUP] 1 [/SUP], Yuanqi Zhao[SUP] 1 4 [/SUP], Bowen Wang[SUP] 5 [/SUP], Jinghong Yang[SUP] 3 [/SUP], Yuqi He[SUP] 1 [/SUP], Ying Wu[SUP] 1 [/SUP], Yuanyuan Wang[SUP] 6 [/SUP], Luoyi Chen[SUP] 1 [/SUP], Arpaporn Chuchuay[SUP] 1 [/SUP], Yuyu You[SUP] 1 [/SUP], Xinhai Zhu[SUP] 7 [/SUP], Xiaojuan Wang[SUP] 8 [/SUP], Ye Chen[SUP] 9 [/SUP], Yanqun Wang[SUP] 3 [/SUP], Yao-Qing Chen[SUP] 6 [/SUP], Yanqiu Yuan[SUP] 10 [/SUP], Jincun Zhao[SUP] 11 12 13 14 15 16 [/SUP], Yang Mao[SUP] 17 18 [/SUP]
Affiliations
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.
. 2024 May 16;15(1):4162.
doi: 10.1038/s41467-024-48503-x. Sequential glycosylations at the multibasic cleavage site of SARS-CoV-2 spike protein regulate viral activity
Shengjun Wang[SUP] #[/SUP][SUP] 1 2 [/SUP], Wei Ran[SUP] #[/SUP][SUP] 3 [/SUP], Lingyu Sun[SUP] #[/SUP][SUP] 1 [/SUP], Qingchi Fan[SUP] 1 [/SUP], Yuanqi Zhao[SUP] 1 4 [/SUP], Bowen Wang[SUP] 5 [/SUP], Jinghong Yang[SUP] 3 [/SUP], Yuqi He[SUP] 1 [/SUP], Ying Wu[SUP] 1 [/SUP], Yuanyuan Wang[SUP] 6 [/SUP], Luoyi Chen[SUP] 1 [/SUP], Arpaporn Chuchuay[SUP] 1 [/SUP], Yuyu You[SUP] 1 [/SUP], Xinhai Zhu[SUP] 7 [/SUP], Xiaojuan Wang[SUP] 8 [/SUP], Ye Chen[SUP] 9 [/SUP], Yanqun Wang[SUP] 3 [/SUP], Yao-Qing Chen[SUP] 6 [/SUP], Yanqiu Yuan[SUP] 10 [/SUP], Jincun Zhao[SUP] 11 12 13 14 15 16 [/SUP], Yang Mao[SUP] 17 18 [/SUP]
Affiliations
- PMID: 38755139
- DOI: 10.1038/s41467-024-48503-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.