2. Academic Validation
  3. SARS-CoV-2 Membrane protein regulates the function of Spike by inhibiting its plasma membrane localization and enzymatic activity of Furin

SARS-CoV-2 Membrane protein regulates the function of Spike by inhibiting its plasma membrane localization and enzymatic activity of Furin

  • Microbiol Res. 2024 May:282:127659. doi: 10.1016/j.micres.2024.127659.
Qi Xiang 1,  Jie Wu 1,  Yuzheng Zhou 2,  Linhao Li 1,  Miao Tian 1,  Guobao Li 3,  Zheng Zhang 4,  Yang Fu 5
Affiliations

Affiliations

  • 1 School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong Province 518055, China.
  • 2 Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong Province 518112, China.
  • 3 Department of Tuberculosis, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen 518112, China. Electronic address: [email protected].
  • 4 Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong Province 518112, China. Electronic address: [email protected].
  • 5 School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong Province 518055, China. Electronic address: [email protected].
PMID: 38430890 DOI: 10.1016/j.micres.2024.127659
Abstract

The presence of a multibasic cleavage site in the Spike protein of SARS-CoV-2 makes it prone to be cleaved by Furin at the S1/S2 junction (aa. 685-686), which enhances the usage of TMPRSS2 to promote cell-cell fusion to form syncytia. Syncytia may contribute to pathology by facilitating viral dissemination, cytopathicity, immune evasion, and inflammation. However, the role of Other SARS-CoV-2 encoding Viral Proteins in syncytia formation remains largely unknown. Here, we report that SARS-CoV-2 M protein effectively inhibits syncytia formation triggered by Spike or its variants (Alpha, Delta, Omicron, etc.) and prevents Spike cleavage into S1 and S2 based on a screen assay of 20 Viral Proteins. Mechanistically, M protein interacts with Furin and inhibits its enzymatic activity, preventing the cleavage of Spike. In addition, M interacts with Spike independent of its cytoplasmic tail, retaining it within the cytoplasm and reducing cell membrane localization. Our findings offer new insights into M protein's role in regulating Spike's function and underscore the importance of functional interplay among Viral Proteins, highlighting potential avenues for SARS-CoV-2 therapy development.

Keywords

Furin; M protein; SARS-CoV-2; Spike; Syncytia.

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