Furin cleavage of the SARS-CoV-2 spike is modulated by O-glycosylation
The SARS-CoV-2 coronavirus responsible for the global pandemic contains a novel furin cleavage site in the spike protein (S) that increases viral infectivity and syncytia formation in cells. Here, we show that O-glycosylation near the furin cleavage site is mediated by members of the GALNT enzyme fa...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2021-11, Vol.118 (47), p.1-7 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
| container_volume | 118 |
| creator | Zhang, Liping Mann, Matthew Syed, Zulfeqhar A. Reynolds, Hayley M. Tian, E. Samara, Nadine L. Zeldin, Darryl C. Tabak, Lawrence A. Hagen, Kelly G. Ten |
| description | The SARS-CoV-2 coronavirus responsible for the global pandemic contains a novel furin cleavage site in the spike protein (S) that increases viral infectivity and syncytia formation in cells. Here, we show that O-glycosylation near the furin cleavage site is mediated by members of the GALNT enzyme family, resulting in decreased furin cleavage and decreased syncytia formation. Moreover, we show that O-glycosylation is dependent on the novel proline at position 681 (P681). Mutations of P681 seen in the highly transmissible alpha and delta variants abrogate O-glycosylation, increase furin cleavage, and increase syncytia formation. Finally, we show that GALNT family members capable of glycosylating S are expressed in human respiratory cells that are targets for SARS-CoV-2 infection. Our results suggest that host O-glycosylation may influence viral infectivity/tropism by modulating furin cleavage of S and provide mechanistic insight into the role of the P681 mutations found in the highly transmissible alpha and delta variants. |
| doi_str_mv | 10.1073/pnas.2109905118 |
| format | Article |
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Ten</creator><creatorcontrib>Zhang, Liping ; Mann, Matthew ; Syed, Zulfeqhar A. ; Reynolds, Hayley M. ; Tian, E. ; Samara, Nadine L. ; Zeldin, Darryl C. ; Tabak, Lawrence A. ; Hagen, Kelly G. Ten</creatorcontrib><description>The SARS-CoV-2 coronavirus responsible for the global pandemic contains a novel furin cleavage site in the spike protein (S) that increases viral infectivity and syncytia formation in cells. Here, we show that O-glycosylation near the furin cleavage site is mediated by members of the GALNT enzyme family, resulting in decreased furin cleavage and decreased syncytia formation. Moreover, we show that O-glycosylation is dependent on the novel proline at position 681 (P681). Mutations of P681 seen in the highly transmissible alpha and delta variants abrogate O-glycosylation, increase furin cleavage, and increase syncytia formation. Finally, we show that GALNT family members capable of glycosylating S are expressed in human respiratory cells that are targets for SARS-CoV-2 infection. Our results suggest that host O-glycosylation may influence viral infectivity/tropism by modulating furin cleavage of S and provide mechanistic insight into the role of the P681 mutations found in the highly transmissible alpha and delta variants.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2109905118</identifier><identifier>PMID: 34732583</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; Biological Sciences ; Cell Fusion ; Cell Line ; Cleavage ; Coronaviruses ; COVID-19 ; Furin ; Furin - metabolism ; Giant Cells ; Glycosylation ; Humans ; Infectivity ; Mutation ; N-Acetylgalactosaminyltransferases - metabolism ; Pandemics ; Polypeptide N-acetylgalactosaminyltransferase ; Proline ; SARS-CoV-2 - genetics ; SARS-CoV-2 - metabolism ; Severe acute respiratory syndrome coronavirus 2 ; Spike Glycoprotein, Coronavirus - genetics ; Spike Glycoprotein, Coronavirus - metabolism ; Spike protein ; Syncytia ; Tropism ; Viral diseases</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2021-11, Vol.118 (47), p.1-7</ispartof><rights>Copyright © 2021 the Author(s). Published by PNAS.</rights><rights>Copyright National Academy of Sciences Nov 23, 2021</rights><rights>Copyright © 2021 the Author(s). Published by PNAS. 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3588-e80052e67e79a443ee4d080130920866471d7321acdbc32a163832041e06a4553</citedby><cites>FETCH-LOGICAL-c3588-e80052e67e79a443ee4d080130920866471d7321acdbc32a163832041e06a4553</cites><orcidid>0000-0001-7152-2939 ; 0000-0002-4261-7856 ; 0000-0001-8637-4975</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/27093986$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/27093986$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34732583$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Liping</creatorcontrib><creatorcontrib>Mann, Matthew</creatorcontrib><creatorcontrib>Syed, Zulfeqhar A.</creatorcontrib><creatorcontrib>Reynolds, Hayley M.</creatorcontrib><creatorcontrib>Tian, E.</creatorcontrib><creatorcontrib>Samara, Nadine L.</creatorcontrib><creatorcontrib>Zeldin, Darryl C.</creatorcontrib><creatorcontrib>Tabak, Lawrence A.</creatorcontrib><creatorcontrib>Hagen, Kelly G. Ten</creatorcontrib><title>Furin cleavage of the SARS-CoV-2 spike is modulated by O-glycosylation</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>The SARS-CoV-2 coronavirus responsible for the global pandemic contains a novel furin cleavage site in the spike protein (S) that increases viral infectivity and syncytia formation in cells. Here, we show that O-glycosylation near the furin cleavage site is mediated by members of the GALNT enzyme family, resulting in decreased furin cleavage and decreased syncytia formation. Moreover, we show that O-glycosylation is dependent on the novel proline at position 681 (P681). Mutations of P681 seen in the highly transmissible alpha and delta variants abrogate O-glycosylation, increase furin cleavage, and increase syncytia formation. Finally, we show that GALNT family members capable of glycosylating S are expressed in human respiratory cells that are targets for SARS-CoV-2 infection. Our results suggest that host O-glycosylation may influence viral infectivity/tropism by modulating furin cleavage of S and provide mechanistic insight into the role of the P681 mutations found in the highly transmissible alpha and delta variants.</description><subject>Animals</subject><subject>Biological Sciences</subject><subject>Cell Fusion</subject><subject>Cell Line</subject><subject>Cleavage</subject><subject>Coronaviruses</subject><subject>COVID-19</subject><subject>Furin</subject><subject>Furin - metabolism</subject><subject>Giant Cells</subject><subject>Glycosylation</subject><subject>Humans</subject><subject>Infectivity</subject><subject>Mutation</subject><subject>N-Acetylgalactosaminyltransferases - metabolism</subject><subject>Pandemics</subject><subject>Polypeptide N-acetylgalactosaminyltransferase</subject><subject>Proline</subject><subject>SARS-CoV-2 - genetics</subject><subject>SARS-CoV-2 - metabolism</subject><subject>Severe acute respiratory syndrome coronavirus 2</subject><subject>Spike Glycoprotein, Coronavirus - genetics</subject><subject>Spike Glycoprotein, Coronavirus - metabolism</subject><subject>Spike protein</subject><subject>Syncytia</subject><subject>Tropism</subject><subject>Viral diseases</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkEtLAzEURoMoWh9rV0rA9bQ3z8lshFKsCkLBqtuQzqTt1OmkJjOF_ntTWquuEnJPvvtxELom0CWQst6qNqFLCWQZCELUEerEO0kkz-AYdQBomihO-Rk6D2EBAJlQcIrOGE8ZFYp10HDY-rLGeWXN2swsdlPczC0e91_HycB9JBSHVflpcRnw0hVtZRpb4MkGj5JZtcld2MSX0tWX6GRqqmCv9ucFeh8-vA2ekpfR4_Og_5LkTCiVWAUgqJWpTTPDObOWF6CAMMgoKCl5SorYjJi8mOSMGiKZYhQ4sSANF4JdoPtd7qqdLG2R27rxptIrXy6N32hnSv1_UpdzPXNrrSRJBdAYcLcP8O6rtaHRC9f6OnbWVEZdoAQjkertqNy7ELydHjYQ0Fvxeite_4qPP27_FjvwP6YjcLMDFqFx_jCPGzOWKcm-AYqbhj4</recordid><startdate>20211123</startdate><enddate>20211123</enddate><creator>Zhang, Liping</creator><creator>Mann, Matthew</creator><creator>Syed, Zulfeqhar A.</creator><creator>Reynolds, Hayley M.</creator><creator>Tian, E.</creator><creator>Samara, Nadine L.</creator><creator>Zeldin, Darryl C.</creator><creator>Tabak, Lawrence A.</creator><creator>Hagen, Kelly G. 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Ten</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Furin cleavage of the SARS-CoV-2 spike is modulated by O-glycosylation</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2021-11-23</date><risdate>2021</risdate><volume>118</volume><issue>47</issue><spage>1</spage><epage>7</epage><pages>1-7</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>The SARS-CoV-2 coronavirus responsible for the global pandemic contains a novel furin cleavage site in the spike protein (S) that increases viral infectivity and syncytia formation in cells. Here, we show that O-glycosylation near the furin cleavage site is mediated by members of the GALNT enzyme family, resulting in decreased furin cleavage and decreased syncytia formation. Moreover, we show that O-glycosylation is dependent on the novel proline at position 681 (P681). Mutations of P681 seen in the highly transmissible alpha and delta variants abrogate O-glycosylation, increase furin cleavage, and increase syncytia formation. Finally, we show that GALNT family members capable of glycosylating S are expressed in human respiratory cells that are targets for SARS-CoV-2 infection. Our results suggest that host O-glycosylation may influence viral infectivity/tropism by modulating furin cleavage of S and provide mechanistic insight into the role of the P681 mutations found in the highly transmissible alpha and delta variants.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>34732583</pmid><doi>10.1073/pnas.2109905118</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0001-7152-2939</orcidid><orcidid>https://orcid.org/0000-0002-4261-7856</orcidid><orcidid>https://orcid.org/0000-0001-8637-4975</orcidid><oa>free_for_read</oa></addata></record> |
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| source | Jstor Complete Legacy; MEDLINE; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Animals Biological Sciences Cell Fusion Cell Line Cleavage Coronaviruses COVID-19 Furin Furin - metabolism Giant Cells Glycosylation Humans Infectivity Mutation N-Acetylgalactosaminyltransferases - metabolism Pandemics Polypeptide N-acetylgalactosaminyltransferase Proline SARS-CoV-2 - genetics SARS-CoV-2 - metabolism Severe acute respiratory syndrome coronavirus 2 Spike Glycoprotein, Coronavirus - genetics Spike Glycoprotein, Coronavirus - metabolism Spike protein Syncytia Tropism Viral diseases |
| title | Furin cleavage of the SARS-CoV-2 spike is modulated by O-glycosylation |
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