A Unique Protease Cleavage Site Predicted in the Spike Protein of the Novel Pneumonia Coronavirus (2019-nCoV) Potentially Related to Viral Transmissibility
Identifieur interne : 000139 ( Pmc/Corpus ); précédent : 000138; suivant : 000140A Unique Protease Cleavage Site Predicted in the Spike Protein of the Novel Pneumonia Coronavirus (2019-nCoV) Potentially Related to Viral Transmissibility
Auteurs : Qiong Wang ; Ye Qiu ; Jin-Yan Li ; Zhi-Jian Zhou ; Ce-Heng Liao ; Xing-Yi GeSource :
- Virologica Sinica [ 1674-0769 ] ; 2020.
Url:
DOI: 10.1007/s12250-020-00212-7
PubMed: NONE
PubMed Central: 7091172
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PMC:7091172Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">A Unique Protease Cleavage Site Predicted in the Spike Protein of the Novel Pneumonia Coronavirus (2019-nCoV) Potentially Related to Viral Transmissibility</title><author><name sortKey="Wang, Qiong" sort="Wang, Qiong" uniqKey="Wang Q" first="Qiong" last="Wang">Qiong Wang</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Qiu, Ye" sort="Qiu, Ye" uniqKey="Qiu Y" first="Ye" last="Qiu">Ye Qiu</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Li, Jin Yan" sort="Li, Jin Yan" uniqKey="Li J" first="Jin-Yan" last="Li">Jin-Yan Li</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Zhou, Zhi Jian" sort="Zhou, Zhi Jian" uniqKey="Zhou Z" first="Zhi-Jian" last="Zhou">Zhi-Jian Zhou</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Liao, Ce Heng" sort="Liao, Ce Heng" uniqKey="Liao C" first="Ce-Heng" last="Liao">Ce-Heng Liao</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Ge, Xing Yi" sort="Ge, Xing Yi" uniqKey="Ge X" first="Xing-Yi" last="Ge">Xing-Yi Ge</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmc">7091172</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7091172</idno><idno type="RBID">PMC:7091172</idno><idno type="doi">10.1007/s12250-020-00212-7</idno><idno type="pmid">NONE</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">000139</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000139</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A Unique Protease Cleavage Site Predicted in the Spike Protein of the Novel Pneumonia Coronavirus (2019-nCoV) Potentially Related to Viral Transmissibility</title><author><name sortKey="Wang, Qiong" sort="Wang, Qiong" uniqKey="Wang Q" first="Qiong" last="Wang">Qiong Wang</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Qiu, Ye" sort="Qiu, Ye" uniqKey="Qiu Y" first="Ye" last="Qiu">Ye Qiu</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Li, Jin Yan" sort="Li, Jin Yan" uniqKey="Li J" first="Jin-Yan" last="Li">Jin-Yan Li</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Zhou, Zhi Jian" sort="Zhou, Zhi Jian" uniqKey="Zhou Z" first="Zhi-Jian" last="Zhou">Zhi-Jian Zhou</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Liao, Ce Heng" sort="Liao, Ce Heng" uniqKey="Liao C" first="Ce-Heng" last="Liao">Ce-Heng Liao</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Ge, Xing Yi" sort="Ge, Xing Yi" uniqKey="Ge X" first="Xing-Yi" last="Ge">Xing-Yi Ge</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author></analytic><series><title level="j">Virologica Sinica</title><idno type="ISSN">1674-0769</idno><idno type="eISSN">1995-820X</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Bertram, S" uniqKey="Bertram S">S Bertram</name></author><author><name sortKey="Glowacka, I" uniqKey="Glowacka I">I Glowacka</name></author><author><name sortKey="Muller, Ma" uniqKey="Muller M">MA Muller</name></author><author><name sortKey="Lavender, H" uniqKey="Lavender H">H Lavender</name></author><author><name sortKey="Gnirss, K" uniqKey="Gnirss K">K Gnirss</name></author><author><name sortKey="Nehlmeier, I" uniqKey="Nehlmeier I">I Nehlmeier</name></author><author><name sortKey="Niemeyer, D" uniqKey="Niemeyer 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Virol Sin</journal-id><journal-id journal-id-type="iso-abbrev">Virol Sin</journal-id><journal-title-group><journal-title>Virologica Sinica</journal-title></journal-title-group><issn pub-type="ppub">1674-0769</issn><issn pub-type="epub">1995-820X</issn><publisher><publisher-name>Springer Singapore</publisher-name><publisher-loc>Singapore</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmc">7091172</article-id><article-id pub-id-type="publisher-id">212</article-id><article-id pub-id-type="doi">10.1007/s12250-020-00212-7</article-id><article-categories><subj-group subj-group-type="heading"><subject>Letter</subject></subj-group></article-categories><title-group><article-title>A Unique Protease Cleavage Site Predicted in the Spike Protein of the Novel Pneumonia Coronavirus (2019-nCoV) Potentially Related to Viral Transmissibility</article-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Wang</surname><given-names>Qiong</given-names></name><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Qiu</surname><given-names>Ye</given-names></name><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Jin-Yan</given-names></name><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Zhou</surname><given-names>Zhi-Jian</given-names></name><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Liao</surname><given-names>Ce-Heng</given-names></name><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0003-3964-5140</contrib-id><name><surname>Ge</surname><given-names>Xing-Yi</given-names></name><address><email>xyge@hnu.edu.cn</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.67293.39</institution-id><institution>Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology, College of Biology,</institution><institution>Hunan University,</institution></institution-wrap>Changsha, 410082 Hunan China</aff></contrib-group><pub-date pub-type="epub"><day>20</day><month>3</month><year>2020</year></pub-date><fpage>1</fpage><lpage>3</lpage><history><date date-type="received"><day>15</day><month>2</month><year>2020</year></date><date date-type="accepted"><day>6</day><month>3</month><year>2020</year></date></history><permissions><copyright-statement>© Wuhan Institute of Virology, CAS 2020</copyright-statement><license><license-p>This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.</license-p></license></permissions></article-meta></front><body><p id="Par1"><bold>Dear Editor,</bold></p><p id="Par2">In December 2019, a novel human coronavirus caused an epidemic of severe pneumonia (Coronavirus Disease 2019, COVID-19) in Wuhan, Hubei, China (Wu <italic>et al.</italic><xref ref-type="bibr" rid="CR12">2020</xref>; Zhu <italic>et al.</italic><xref ref-type="bibr" rid="CR15">2020</xref>). So far, this virus has spread to all areas of China and even to other countries. The epidemic has caused 67,102 confirmed infections with 1526 fatal cases worldwide by February 14th, 2020. The viral infection incubation period varies from 2 to 14 days and typical clinical symptoms are fever, dry cough, dyspnea, headache, and pneumonia. Disease onset may result in progressive respiratory failure due to alveolar damage and even death (Chan <italic>et al.</italic><xref ref-type="bibr" rid="CR3">2020</xref>; Chen <italic>et al.</italic><xref ref-type="bibr" rid="CR4">2020</xref>; Huang <italic>et al.</italic><xref ref-type="bibr" rid="CR6">2020</xref>).</p><p id="Par3">The nomenclature for this coronavirus is still controversial. It was initially named as 2019-nCoV, indicating that it is a novel coronavirus identified in the year of 2019. Recently, the International Committee on Taxonomy of Viruses (ICTV) has suggested to name this virus as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on its phylogenetic relationship with SARS-CoV. However, many researchers point out that the name SARS-CoV-2 implies this virus as a pathogen of SARS, but actually, COVID-19 is a disease different from SARS, and the name SARS-CoV-2 may mislead the treatment and prevention of COVID-19. Hence, a new name, human coronavirus 2019 (HCoV-19), has been suggested, which is more appropriate and consistent with the disease name of COVID-19 (Jiang <italic>et al.</italic><xref ref-type="bibr" rid="CR7">2020</xref>). Nevertheless, to avoid potential confusions, we use 2019-nCoV to indicate the new coronavirus in this letter, mimicking most articles published recently.</p><p id="Par4">Coronaviruses are enveloped non-segmented positive sense RNA viruses belonging to the genus <italic>Betacoronavirus</italic> of the subfamily <italic>Orthocoronavirinae</italic> in the family <italic>Coronaviridae</italic>. Based on the phylogenetic tree, 2019-nCoV is clustered into the <italic>Sarbecovirus</italic> subgenus with other severe acute respiratory syndrome-related coronaviruses (SARSr-CoVs), such as SARS-CoV and bat SARSr-CoV (Zhou <italic>et al.</italic><xref ref-type="bibr" rid="CR14">2020</xref>). Compared to other human coronaviruses, 2019-nCoV emerges several unique features. First, the mortality of 2019-nCoV infection is estimated to be 3.06% which is much lower than that of SARS-CoV (10%) and MERS-CoV (37%). Second, SARS-CoV-2 has a basic reproduction rate (R<sub>0</sub>) of 3.3–5.5, higher than those of SARS-CoV (2–5) and MERS-CoV (2.7–3.9), indicating a higher transmissibility of SARS-CoV-2 than other human coronaviruses (Lipsitch <italic>et al.</italic><xref ref-type="bibr" rid="CR10">2003</xref>; Wallinga <xref ref-type="bibr" rid="CR11">2004</xref>; Lin <italic>et al.</italic><xref ref-type="bibr" rid="CR9">2018</xref>). The underlying mechanism determining these features is still unclear and more relevant studies are urged considering the serious 2019-nCoV epidemic recently.</p><p id="Par5">Receptor recognition is an important factor determining host range and cross-species infection of viruses. For coronaviruses, their receptor binding and subsequent internalization mainly depend on the spike protein (S protein) anchored in the viral envelope. All coronavirus S proteins consist of three domains: an extracellular domain (EC), a transmembrane anchor domain and a short intracellular tail. EC contains two functional subunits, a receptor-binding subunit (S1) and a membrane-fusion subunit (S2). S1 contains two independent domains, an N-terminal domain (S1-NTD) and receptor binding domain (RBD), which plays a key role in receptor recognition and binding (Heald-Sargent and Gallagher <xref ref-type="bibr" rid="CR5">2012</xref>; Li <xref ref-type="bibr" rid="CR8">2012</xref>). During host-virus membrane fusion, spikes protein is cleaved at the S1/S2 boundary by host proteases, releasing the spike fusion peptide, which is necessary for virus entry. The host proteases for S protein cleavage vary among different coronaviruses, which is a key factor determining the epidemiological and pathological features of virus, including host range, tissue tropism, transmissibility and mortality. For instance, a variety of human proteases, such as trypsin, tryptase Clara, human airway trypsin-like protease (HAT) and transmembrane protease serine 2 (TMPRSS2), are known to cleave and activate the S protein of SARS-CoV (Bosch <italic>et al.</italic><xref ref-type="bibr" rid="CR2">2008</xref>; Bertram <italic>et al.</italic><xref ref-type="bibr" rid="CR1">2011</xref>). These proteases are widely expressed in many important organs, which is critical reason for the systematic infection, serious pathogenicity and high mortality of SARS-CoV. Laboratory studies also demonstrated that the IBV Beaudette strain, compared to other IBV strains, have an extended tropism, which infects not only primary chicken cells but also many other cell lines, due to containing an additional consensus furin cleavage site on its S protein (Yamada and Liu <xref ref-type="bibr" rid="CR13">2009</xref>).</p><p id="Par6">In this study, we discovered one deletion and three insertions in 2019-nCoV S protein by amino acid sequence alignment. Notably, four additional amino acid residues (–PRRA–) were inserted between S1 and S2 subunits, potentially affecting the cleavage of S protein as our hypothesis (Fig. <xref rid="Fig1" ref-type="fig">1</xref>A). To verify our speculation, we comprehensively predicted the protease cleavage sites on different coronavirus S protein by using the ProP 1.0 server (<ext-link ext-link-type="uri" xlink:href="http://www.cbs.dtu.dk/services/ProP/">www.cbs.dtu.dk/services/ProP/</ext-link>). This server is designed to predict arginine and lysine propeptide cleavage sites in eukaryotic protein sequences by using an ensemble of neural networks. As a result, 2019-nCoV S protein showed a unique furin cleavage (–RRAR–) within the S1/S2 domain which was overlapped with insertion described above (Fig. <xref rid="Fig1" ref-type="fig">1</xref>B). This furin cleavage site was located between the residues 682 and 685, distinct from SARS-CoV and all other SARS-like coronaviruses which only contain a trypsin or TMPRSS2 cleavage site at R667 (corresponding to residues 685 in 2019-nCoV S) (Fig. <xref rid="Fig1" ref-type="fig">1</xref>B). Furin is a protease ubiquitously expressed in a variety of organs and tissues, including brain, lung, gastrointestinal tract, liver, pancreas and reproductive tissues. With the furin cleavage site on the S protein, 2019-nCoV probably gains ability to infect organs or tissues insensitive to other coronaviruses, leading to systematic infection of 2019-nCoV in the body. Even worse, the wide distribution of 2019-nCoV in a patient body may release the virus into the environment via more diverse ways, severely enhancing the transmission of 2019-nCoV. This hypothesis is supported by the current reports about the trace of 2019-nCoV in some place distinct from other coronaviruses, such as feces and eyes. However, these speculations are mainly based on our sequence studies, and further functional studies are required to characterize how these differences affect the functionality and pathogenesis of 2019-nCoV.<fig id="Fig1"><label>Fig. 1</label><caption><p>The predicted cleavage site between S1/S2 in the spike protein of 2019-nCoV. <bold>A</bold> The PRRA insertion (underlined) in the S of 2019-nCoV. <bold>B</bold> Prediction of a furin-specific cleavage site (indicated by a red arrow) in the S protein of 2019-nCoV.</p></caption><graphic xlink:href="12250_2020_212_Fig1_HTML" id="MO1"></graphic></fig></p><p id="Par7">In summary, our sequence analysis on the S protein of 2019-nCoV has predicted a novel furin cleavage site at S1/S2 linkage. The ubiquitous expression of furin in different organs and tissues may be a reason for the high transmissibility and pathogenicity of 2019-nCoV observed in the current epidemic. However, since our findings were mainly based on bioinformatic analysis, more laboratory studies on 2019-nCoV in cell and animal models are required to verify our speculations and to avoid any bias.</p></body><back><fn-group><fn><p>Qiong Wang and Ye Qiu have authors contributed equally to this work.</p></fn></fn-group><ack><title>Acknowledgements</title><p>This work was jointly funded by the National Key Research and Development Program of China (Grant No. 2017YFD0500104), National Natural Science Foundation of China (Grant Nos. 31470260, 81902070), the Science Fund for Distinguished Young Scholars of Hunan Province (Grant No. 2019JJ20004), the Provincial Natural Science Foundation of Hunan Province (Grant Nos. 2019JJ50035, 2020SK3001) and the Fundamental Research Funds for the Central Universities of China (Grant No. 531107051162).</p></ack><notes><title>Compliance with Ethical Standards</title><notes notes-type="COI-statement"><title>Conflict of interest</title><p id="Par8">The 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|flux= Pmc
|étape= Corpus
|type= RBID
|clé= PMC:7091172
|texte= A Unique Protease Cleavage Site Predicted in the Spike Protein of the Novel Pneumonia Coronavirus (2019-nCoV) Potentially Related to Viral Transmissibility
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/RBID.i -Sk "pubmed:NONE" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd \
| NlmPubMed2Wicri -a CovidV2
| This area was generated with Dilib version V0.6.33. |  |