OmniVira

Spike substitution T813S increases Sarbecovirus fusogenicity by enhancing the usage of TMPRSS2.

Yong Ma1 Pengbin Li1 Yunqi Hu1 Tianyi Qiu2 Lixiang Wang3 Hongjie Lu1 Kexin Lv1 Mengxin Xu1 Jiaxin Zhuang4 Xue Liu4 Suhua He5 Bing He1 Shuning Liu1 Lin Liu1 Yuanyuan Wang1 Xinyu Yue1 Yanmei Zhai1 Wanyu Luo1 Haoting Mai1 Yu Kuang1 Shifeng Chen6 Feng Ye6 Na Zhou6 Wenjing Zhao4 Jun Chen3 Shoudeng Chen5 Xiaoli Xiong7 Mang Shi4 Ji-An Pan4 Yao-Qing Chen1,8
Affiliations 8 institutions
  1. School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, China.
  2. Institute of Clinical Science, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
  3. Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  4. The Center for Infection and Immunity Study and Molecular Cancer Research Center, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen, China.
  5. Molecular Imaging Center, Guangdong Provincial Key Laboratory of Biomedical Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China.
  6. The 74(th) Group Army Hospital, Guangzhou, China.
  7. State Key Laboratory of Respiratory Disease, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
  8. National Medical Products Administration Key Laboratory for Quality Monitoring and Evaluation of Vaccines and Biological Products, Sun Yat-sen University, Guanzhou, China.
PMID37196033 DOI10.1371/journal.ppat.1011123 Year2023 Journal PLoS pathogens PLoS Pathog Languageeng Statusepublish

Abstract

SARS-CoV Spike (S) protein shares considerable homology with SARS-CoV-2 S, especially in the conserved S2 subunit (S2). S protein mediates coronavirus receptor binding and membrane fusion, and the latter activity can greatly influence coronavirus infection. We observed that SARS-CoV S is less effective in inducing membrane fusion compared with SARS-CoV-2 S. We identify that S813T mutation is sufficient in S2 interfering with the cleavage of SARS-CoV-2 S by TMPRSS2, reducing spike fusogenicity and pseudoparticle entry. Conversely, the mutation of T813S in SARS-CoV S increased fusion ability and viral replication. Our data suggested that residue 813 in the S was critical for the proteolytic activation, and the change from threonine to serine at 813 position might be an evolutionary feature adopted by SARS-2-related viruses. This finding deepened the understanding of Spike fusogenicity and could provide a new perspective for exploring Sarbecovirus' evolution.

Supporting text Virus Host Location
COVID-19 425 Severe acute respiratory syndrome-related coronavirus 78 Humans 1440 Proteolysis 5 SARS-CoV-2 453 Serine Endopeptidases 12 Spike Glycoprotein, Coronavirus 274 Virus Internalization 100 Virus Replication 191 spike protein, SARS-CoV-2 157 TMPRSS2 protein, human 10

Evidence records

1 total
Functional Mechanism
1 records · 1 evidence types
Evidence type Molecular Adaptation
1 records
OVE6983 Molecular Adaptation
Key finding

The T813S substitution in the Spike protein of SARS-CoV increases membrane fusion and viral replication, representing an evolutionary adaptation among Sarbecoviruses.

Virus
Severe Acute Respiratory Syndrome Coronavirus Severe acute respiratory syndrome coronavirus 2 Sarbecovirus
Host
Not specified
Location
Not specified
Supporting text

Conversely, the mutation of T813S in SARS-CoV S increased fusion ability and viral replication. Our data suggested that residue 813 in the S was critical for the proteolytic activation, and the change from threonine to serine at 813 position might be an evolutionary feature adopted by SARS-2-related viruses.

Genes or proteins
Spike | S
Mutations
T813S
Mechanism types
host entry | replication adaptation