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

Xiang，Qi1; Wu，Jie1; Zhou，Yuzheng2; Li，Linhao1; Tian，Miao1; Li，Guobao3; Zhang，Zheng2; Fu，Yang1

2024-05-01

10.1016/j.micres.2024.127659

Microbiological Research   影响因子和分区

0944-5013

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.

Furin M protein SARS-CoV-2 Spike Syncytia

EI

英语

第一 ; 通讯

MICROBIOLOGY

2-s2.0-85186534495

Scopus

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

Xiang，Qi,Wu，Jie,Zhou，Yuzheng,et al. SARS-CoV-2 Membrane protein regulates the function of Spike by inhibiting its plasma membrane localization and enzymatic activity of Furin[J]. Microbiological Research,2024,282.

Xiang，Qi.,Wu，Jie.,Zhou，Yuzheng.,Li，Linhao.,Tian，Miao.,...&Fu，Yang.(2024).SARS-CoV-2 Membrane protein regulates the function of Spike by inhibiting its plasma membrane localization and enzymatic activity of Furin.Microbiological Research,282.

Xiang，Qi,et al."SARS-CoV-2 Membrane protein regulates the function of Spike by inhibiting its plasma membrane localization and enzymatic activity of Furin".Microbiological Research 282(2024).