Sequential glycosylations at the multibasic cleavage site of SARS-CoV-2 spike protein regulate viral activity

Wang，Shengjun1,15; Ran，Wei2; Sun，Lingyu1; Fan，Qingchi1; Zhao，Yuanqi1,16; Wang，Bowen3; Yang，Jinghong2; He，Yuqi1; Wu，Ying1; Wang，Yuanyuan4; Chen，Luoyi1; Chuchuay，Arpaporn1; You，Yuyu1; Zhu，Xinhai5; Wang，Xiaojuan6; Chen，Ye7; Wang，Yanqun2; Chen，Yao Qing4; Yuan，Yanqiu8; Zhao，Jincun2,9,10,11,12,13; Mao，Yang1,14

2024-12-01

10.1038/s41467-024-48503-x

Nature Communications   影响因子和分区

2041-1723

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.

英语

其他

2-s2.0-85193546231

Scopus

1.School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou,China
2.State Key Laboratory of Respiratory Disease,National Clinical Research Center for Respiratory Disease,Guangzhou Institute of Respiratory Health,The First Affiliated Hospital of Guangzhou Medical University,Guangzhou,China
3.College of Life Science,Northwest University,Xi’an,China
4.School of Public Health (Shenzhen),Shenzhen Campus of Sun Yat-sen University,Shenzhen,China
5.Instrumental Analysis & amp; Research Center,Sun Yat-sen University,Guangzhou,China
6.Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou,China
7.Key Laboratory of Fujian-Taiwan Animal Pathogen Biology,College of Animal Sciences,Fujian Agriculture and Forestry University,Fuzhou,China
8.State Key Laboratory of Anti-Infective Drug Discovery and Development,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou,China
9.Institute of Infectious Disease,Guangzhou Eighth People’s Hospital of Guangzhou Medical University,Guangzhou,China
10.Guangzhou Laboratory,Bio-island,Guangzhou,China
11.The Second Affiliated Hospital,School of Medicine,Southern University of Science and Technology,Shenzhen,China
12.Shanghai Institute for Advanced Immunochemical Studies,School of Life Science and Technology,ShanghaiTech University,Shanghai,China
13.Institute for Hepatology,National Clinical Research Center for Infectious Disease,Shenzhen Third People’s Hospital,Shenzhen,China
14.Guangdong Provincial Key Laboratory of Drug Non-Clinical Evaluation and Research,Guangzhou,China
15.School of Health and Life Sciences,University of Health and Rehabilitation Sciences,Qingdao,China
16.Foshan Institute for Food and Drug Control,Foshan,China

Wang，Shengjun,Ran，Wei,Sun，Lingyu,et al. Sequential glycosylations at the multibasic cleavage site of SARS-CoV-2 spike protein regulate viral activity[J]. Nature Communications,2024,15(1).

Wang，Shengjun.,Ran，Wei.,Sun，Lingyu.,Fan，Qingchi.,Zhao，Yuanqi.,...&Mao，Yang.(2024).Sequential glycosylations at the multibasic cleavage site of SARS-CoV-2 spike protein regulate viral activity.Nature Communications,15(1).

Wang，Shengjun,et al."Sequential glycosylations at the multibasic cleavage site of SARS-CoV-2 spike protein regulate viral activity".Nature Communications 15.1(2024).