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Proc Natl Acad Sci U S A
. 2026 Feb 3;123(5):e2504517123.
doi: 10.1073/pnas.2504517123. Epub 2026 Jan 30.
SARS-CoV-2 S assembly into virions facilitated by host ERM proteins
Jiaming Wang # 1 , Wanbo Tai # 2 3 4 , Zhaoyang Wang 2 3 4 , Wenxin Dai 1 , Mingrui Yang 1 , Jiajian Guo 1 , Pengfei He 1 , Yanan Nan 1 , Tianyu Li 1 , Shuqi Zhou 1 , Dongxiao Cui 1 , Yiqun Li 1 , Cuiyan Ma 1 , Yue Zhang 1 , Dongdong Li 5 , Zhengdan Zhu 5 , Kexin Chu 5 , Dongdong Wang 5 , Songhui Yang 6 , Xinyu Zhuang 6 , Mingyao Tian 6 , Mingkang Huang 3 , Xianwen Zhang 3 , Gong Cheng 2 3 4 7 , Wenfu Ma 1
Affiliations
The host cell cytoskeleton plays a critical role in the SARS-CoV-2 life cycle, though the underlying mechanisms remain poorly understood. This study investigates the interaction between the SARS-CoV-2 spike (S) protein and the cytoskeleton-associated ezrin-radixin-moesin (ERM) proteins through biochemical and structural characterization. A previously unidentified ERM-binding motif on the SARS-CoV-2 S protein is identified, revealing that S-ERM interactions are specifically conserved among highly pathogenic coronaviruses, including SARS-CoV, MERS-CoV, and SARS-CoV-2. Functionally, these interactions facilitate S packaging into virions by directing it to assembly sites, utilizing ERM's affinity for negatively curved membranes, akin to its role in cell surface protrusions. Silencing ERM expression significantly reduces SARS-CoV-2 titer, highlighting its essential role in viral propagation. Additionally, leveraging the established role of COPI-mediated trafficking in S localization, a compound is developed to disrupt S-COPI binding, promoting S secretion to the cell surface and effectively reducing viral titers. Our findings revealed a critical host-pathogen interaction that drives S incorporation into virions and identified ERM proteins as key facilitators of coronavirus assembly. Furthermore, our study suggests an antiviral strategy by targeting the S-COPI trafficking pathway. These insights advanced our understanding of coronavirus-host interactions and provided a potential therapeutic approach against SARS-CoV-2 and other highly pathogenic coronaviruses.
Keywords: ERM proteins; SARS-CoV-2; spike; structural biology; viral assembly.
. 2026 Feb 3;123(5):e2504517123.
doi: 10.1073/pnas.2504517123. Epub 2026 Jan 30.
SARS-CoV-2 S assembly into virions facilitated by host ERM proteins
Jiaming Wang # 1 , Wanbo Tai # 2 3 4 , Zhaoyang Wang 2 3 4 , Wenxin Dai 1 , Mingrui Yang 1 , Jiajian Guo 1 , Pengfei He 1 , Yanan Nan 1 , Tianyu Li 1 , Shuqi Zhou 1 , Dongxiao Cui 1 , Yiqun Li 1 , Cuiyan Ma 1 , Yue Zhang 1 , Dongdong Li 5 , Zhengdan Zhu 5 , Kexin Chu 5 , Dongdong Wang 5 , Songhui Yang 6 , Xinyu Zhuang 6 , Mingyao Tian 6 , Mingkang Huang 3 , Xianwen Zhang 3 , Gong Cheng 2 3 4 7 , Wenfu Ma 1
Affiliations
- PMID: 41615754
- DOI: 10.1073/pnas.2504517123
The host cell cytoskeleton plays a critical role in the SARS-CoV-2 life cycle, though the underlying mechanisms remain poorly understood. This study investigates the interaction between the SARS-CoV-2 spike (S) protein and the cytoskeleton-associated ezrin-radixin-moesin (ERM) proteins through biochemical and structural characterization. A previously unidentified ERM-binding motif on the SARS-CoV-2 S protein is identified, revealing that S-ERM interactions are specifically conserved among highly pathogenic coronaviruses, including SARS-CoV, MERS-CoV, and SARS-CoV-2. Functionally, these interactions facilitate S packaging into virions by directing it to assembly sites, utilizing ERM's affinity for negatively curved membranes, akin to its role in cell surface protrusions. Silencing ERM expression significantly reduces SARS-CoV-2 titer, highlighting its essential role in viral propagation. Additionally, leveraging the established role of COPI-mediated trafficking in S localization, a compound is developed to disrupt S-COPI binding, promoting S secretion to the cell surface and effectively reducing viral titers. Our findings revealed a critical host-pathogen interaction that drives S incorporation into virions and identified ERM proteins as key facilitators of coronavirus assembly. Furthermore, our study suggests an antiviral strategy by targeting the S-COPI trafficking pathway. These insights advanced our understanding of coronavirus-host interactions and provided a potential therapeutic approach against SARS-CoV-2 and other highly pathogenic coronaviruses.
Keywords: ERM proteins; SARS-CoV-2; spike; structural biology; viral assembly.