The spike protein of severe acute respiratory syndrome (SARS) is cleaved in virus infected Vero-E6 cells

Wu, Xiao Dong; Shang, Bo; Yang, Rui; Yu, Hao; Zhi, Hai; Shen, Xu; Ji, Yong; Lin, Ying; Wu, Yuan; Guo, Lin; Tian, Lin; Gan, Xiaoqing; Yang, Sheng; Jiang, Wei; Dai, Er Hei; Wang, Xiao Yi; Jiang, Hua; Xie, Yuyuan; Zhu, Xuehua; Pei, Gang; Li, Lin; Wu, Jia; Sun, Bing

doi:10.1038/sj.cr.7290240

Cited by 59 publications

(55 citation statements)

References 20 publications

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“…Although other investigators reported the lack of proS processing [27][28][29][30], this report and others [31,32] detected CTFs by transient transfection of recombinant spike glycoprotein. Although other investigators reported the lack of proS processing [27][28][29][30], this report and others [31,32] detected CTFs by transient transfection of recombinant spike glycoprotein.…”

Section: Discussioncontrasting

confidence: 56%

Implication of proprotein convertases in the processing and spread of severe acute respiratory syndrome coronavirus

Bergeron

Vincent

Wickham

et al. 2005

Biochemical and Biophysical Research Communications

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Severe acute respiratory syndrome coronavirus (SARS-CoV) is the etiological agent of SARS. Analysis of SARS-CoV spike glycoprotein (S) using recombinant plasmid and virus infections demonstrated that the S-precursor (proS) exists as a approximately 190 kDa endoplasmic reticulum form and a approximately 210 kDa Golgi-modified form. ProS is subsequently processed into two C-terminal proteins of approximately 110 and approximately 80 kDa. The membrane-bound proprotein convertases (PCs) furin, PC7 or PC5B enhanced the production of the approximately 80 kDa protein. In agreement, proS processing, cytopathic effects, and viral titers were enhanced in recombinant Vero E6 cells overexpressing furin, PC7 or PC5B. The convertase inhibitor dec-RVKR-cmk significantly reduced proS cleavage and viral titers of SARS-CoV infected cells. In addition, inhibition of processing by dec-RVKR-cmk completely abrogated the virus-induced cellular cytopathicity. A fluorogenically quenched synthetic peptide encompassing Arg(761) of the spike glycoprotein was efficiently cleaved by furin and the cleavage was inhibited by EDTA and dec-RVKR-cmk. Taken together, our data indicate that furin or PC-mediated processing plays a critical role in SARS-CoV spread and cytopathicity, and inhibitors of the PCs represent potential therapeutic anti-SARS-CoV agents.

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Section: Discussioncontrasting

confidence: 56%

Implication of proprotein convertases in the processing and spread of severe acute respiratory syndrome coronavirus

Bergeron

Vincent

Wickham

et al. 2005

Biochemical and Biophysical Research Communications

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“…Nevertheless, a recent study detected a cleaved S2 fragment in the lysate of cells infected with SARS-CoV, suggesting proteolytic processing of S protein of SARS-CoV in host cells. The proposed cleavage site in SARS-CoV (RS 667-668 ) also is found in bat-SARS-CoV (RS 653-654 ) (27). Further studies are required to determine whether the S protein of bat-SARSCoV also is cleaved into S1 and S2 subunits.…”

Section: Wild Animal Surveillance Identification Of Bat-sars-cov Anmentioning

confidence: 99%

Severe acute respiratory syndrome coronavirus-like virus in Chinese horseshoe bats

Lau

Woo

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

1,411

1,425

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“…As a new member of the coronavirus family, SARS-CoV shares with other coronaviruses some similarity and common features in the amino acid sequences of the S protein [8]. It has been found that the S protein of SARS-CoV is posttranslationally cleaved into S1 and S2 functional domains in the process of viral infection [9]. However, the impact of this cleavage on viral infectivity remains unclear [10].…”

Section: Sars-cov; Spike Protein; Protease Factor Xa; Protease Inhibimentioning

confidence: 99%

Cleavage of spike protein of SARS coronavirus by protease factor Xa is associated with viral infectivity

Kao

Zhou

et al. 2007

Biochemical and Biophysical Research Communications

127

125

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The spike (S) protein of SARS coronavirus (SARS-CoV) has been known to recognize and bind to host receptors, whose conformational changes then facilitates fusion between the viral envelope and host cell membrane, leading to viral entry into target cells. However, other functions of SARS-CoV S protein such as proteolytic cleavage and its implications to viral infection are incompletely understood. In this study, we demonstrated that the infection of SARS-CoV and a pseudovirus bearing the S protein of SARS-CoV was inhibited by a protease inhibitor Ben-HCl. Also, the protease Factor Xa, a target of Ben-HCl abundantly expressed in infected cells, was able to cleave the recombinant and pseudoviral S protein into S1 and S2 subunits, and the cleavage was inhibited by Ben-HCl. Furthermore, this cleavage correlated with the infectivity of the pseudovirus. Taken together, our study suggests a plausible mechanism by which SARS-CoV cleaves its S protein to facilitate viral infection. Keywords SARS-CoV; Spike protein; Protease Factor Xa; Protease inhibitor; Cleavage of S proteinSevere acute respiratory syndrome (SARS) is a novel life-threatening infectious disease caused by SARS-coronavirus (SARS-CoV) [1]. Viral spike (S) protein is a multifunctional protein that plays pivotal roles in the biology and pathogenesis of SARS-CoV. The N-terminal region of the S protein has been demonstrated to mediate viral infection, by binding through the receptor-binding domain (RBD) to a cellular receptor angiotensin-converting enzyme 2 (ACE2) [2], and subsequently inducing virus-cell membrane fusion, which involves two domains in the C-terminal region of the S protein named heptad repeat (HR) 1 and 2 [3]. However, other functions of the S protein that are important in viral infection have not yet been defined. * Corresponding author: Fax: +852 2855 1241; E-mail address: bzheng@hkucc.hku.hk. (B.J. Zheng). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. In most other members of the coronavirus family, such as human coronavirus HCoV-OC43 and bovine coronaviruses BCoV, the S protein may be post-translationally cleaved into two fragments, S1 (receptor binding domain) and S2 (membrane fusion domain) [4,5]. Studies in other coronaviruses have further elucidated that conformational changes of the S protein can be induced at 37 °C and pH 8.0, accompanied by the cleavage of S1 and S2, which triggers virus-cell membrane fusion [6,7]. As a new member of the coronavirus family, SARS-CoV shares with other coronaviruses some similarity and common features in the amino acid sequences of the S protein [8]. It...

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The spike protein of severe acute respiratory syndrome (SARS) is cleaved in virus infected Vero-E6 cells

Cited by 59 publications

References 20 publications

Implication of proprotein convertases in the processing and spread of severe acute respiratory syndrome coronavirus

Implication of proprotein convertases in the processing and spread of severe acute respiratory syndrome coronavirus

Severe acute respiratory syndrome coronavirus-like virus in Chinese horseshoe bats

Cleavage of spike protein of SARS coronavirus by protease factor Xa is associated with viral infectivity

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