SARS-CoV-2 Disrupts Splicing, Translation, and Protein Trafficking to Suppress Host Defenses
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently identified coronavirus that causes the respiratory disease known as coronavirus disease 2019 (COVID-19). Despite the urgent need, we still do not fully understand the molecular basis of SARS-CoV-2 pathogenesis. Here, we compr...
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| Veröffentlicht in: | Cell 2020-11, Vol.183 (5), p.1325-1339.e21 |
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| creator | Banerjee, Abhik K. Blanco, Mario R. Bruce, Emily A. Honson, Drew D. Chen, Linlin M. Chow, Amy Bhat, Prashant Ollikainen, Noah Quinodoz, Sofia A. Loney, Colin Thai, Jasmine Miller, Zachary D. Lin, Aaron E. Schmidt, Madaline M. Stewart, Douglas G. Goldfarb, Daniel De Lorenzo, Giuditta Rihn, Suzannah J. Voorhees, Rebecca M. Botten, Jason W. Majumdar, Devdoot Guttman, Mitchell |
| description | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently identified coronavirus that causes the respiratory disease known as coronavirus disease 2019 (COVID-19). Despite the urgent need, we still do not fully understand the molecular basis of SARS-CoV-2 pathogenesis. Here, we comprehensively define the interactions between SARS-CoV-2 proteins and human RNAs. NSP16 binds to the mRNA recognition domains of the U1 and U2 splicing RNAs and acts to suppress global mRNA splicing upon SARS-CoV-2 infection. NSP1 binds to 18S ribosomal RNA in the mRNA entry channel of the ribosome and leads to global inhibition of mRNA translation upon infection. Finally, NSP8 and NSP9 bind to the 7SL RNA in the signal recognition particle and interfere with protein trafficking to the cell membrane upon infection. Disruption of each of these essential cellular functions acts to suppress the interferon response to viral infection. Our results uncover a multipronged strategy utilized by SARS-CoV-2 to antagonize essential cellular processes to suppress host defenses.
[Display omitted]
•NSP16 binds mRNA recognition domains of U1/U2 snRNAs and disrupts mRNA splicing•NSP1 binds in the mRNA entry channel of the ribosome to disrupt protein translation•NSP8 and NSP9 bind the signal recognition particle and disrupt protein trafficking•These disruptions of protein production suppress the interferon response to infection
SARS-CoV-2 proteins directly engage host RNAs to dysregulate essential steps of protein production and suppress the interferon response. |
| doi_str_mv | 10.1016/j.cell.2020.10.004 |
| format | Article |
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[Display omitted]
•NSP16 binds mRNA recognition domains of U1/U2 snRNAs and disrupts mRNA splicing•NSP1 binds in the mRNA entry channel of the ribosome to disrupt protein translation•NSP8 and NSP9 bind the signal recognition particle and disrupt protein trafficking•These disruptions of protein production suppress the interferon response to infection
SARS-CoV-2 proteins directly engage host RNAs to dysregulate essential steps of protein production and suppress the interferon response.</description><identifier>ISSN: 0092-8674</identifier><identifier>ISSN: 1097-4172</identifier><identifier>EISSN: 1097-4172</identifier><identifier>DOI: 10.1016/j.cell.2020.10.004</identifier><identifier>PMID: 33080218</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>A549 Cells ; Animals ; Chlorocebus aethiops ; COVID-19 - metabolism ; COVID-19 - virology ; HEK293 Cells ; Host-Pathogen Interactions ; Humans ; interferon ; Interferons - metabolism ; mRNA splicing ; NSP1 ; NSP16 ; NSP8 ; NSP9 ; Protein Biosynthesis ; protein trafficking ; Protein Transport ; RNA Splicing ; RNA, Messenger - metabolism ; RNA, Ribosomal, 18S - metabolism ; RNA, Small Cytoplasmic - chemistry ; RNA, Small Cytoplasmic - metabolism ; RNA-protein interactions ; SARS-CoV-2 ; SARS-CoV-2 - metabolism ; Signal Recognition Particle - chemistry ; Signal Recognition Particle - metabolism ; translation ; Vero Cells ; Viral Nonstructural Proteins - chemistry ; Viral Nonstructural Proteins - metabolism</subject><ispartof>Cell, 2020-11, Vol.183 (5), p.1325-1339.e21</ispartof><rights>2020 The Authors</rights><rights>Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.</rights><rights>2020 The Authors 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c549t-f95d678177779d815683357dcdbae968aeb2009cd8f3e5423eff9705737269bb3</citedby><cites>FETCH-LOGICAL-c549t-f95d678177779d815683357dcdbae968aeb2009cd8f3e5423eff9705737269bb3</cites><orcidid>0000-0002-4654-8974 ; 0000-0001-6014-387X ; 0000-0003-1862-5204 ; 0000-0001-7400-4125 ; 0000-0002-9797-0104 ; 0000-0001-6662-6258 ; 0000-0003-3893-3466 ; 0000-0002-8766-2378 ; 0000-0001-9495-4056 ; 0000-0002-2541-3851 ; 0000-0001-6839-0306 ; 0000-0003-4748-9352 ; 0000-0003-1640-2293 ; 0000-0002-2736-8740 ; 0000-0003-4503-0118 ; 0000-0003-3832-4871 ; 0000-0002-0508-1781 ; 0000-0001-8391-370X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0092867420313106$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33080218$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Banerjee, Abhik K.</creatorcontrib><creatorcontrib>Blanco, Mario R.</creatorcontrib><creatorcontrib>Bruce, Emily A.</creatorcontrib><creatorcontrib>Honson, Drew D.</creatorcontrib><creatorcontrib>Chen, Linlin M.</creatorcontrib><creatorcontrib>Chow, Amy</creatorcontrib><creatorcontrib>Bhat, Prashant</creatorcontrib><creatorcontrib>Ollikainen, Noah</creatorcontrib><creatorcontrib>Quinodoz, Sofia A.</creatorcontrib><creatorcontrib>Loney, Colin</creatorcontrib><creatorcontrib>Thai, Jasmine</creatorcontrib><creatorcontrib>Miller, Zachary D.</creatorcontrib><creatorcontrib>Lin, Aaron E.</creatorcontrib><creatorcontrib>Schmidt, Madaline M.</creatorcontrib><creatorcontrib>Stewart, Douglas G.</creatorcontrib><creatorcontrib>Goldfarb, Daniel</creatorcontrib><creatorcontrib>De Lorenzo, Giuditta</creatorcontrib><creatorcontrib>Rihn, Suzannah J.</creatorcontrib><creatorcontrib>Voorhees, Rebecca M.</creatorcontrib><creatorcontrib>Botten, Jason W.</creatorcontrib><creatorcontrib>Majumdar, Devdoot</creatorcontrib><creatorcontrib>Guttman, Mitchell</creatorcontrib><title>SARS-CoV-2 Disrupts Splicing, Translation, and Protein Trafficking to Suppress Host Defenses</title><title>Cell</title><addtitle>Cell</addtitle><description>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently identified coronavirus that causes the respiratory disease known as coronavirus disease 2019 (COVID-19). Despite the urgent need, we still do not fully understand the molecular basis of SARS-CoV-2 pathogenesis. Here, we comprehensively define the interactions between SARS-CoV-2 proteins and human RNAs. NSP16 binds to the mRNA recognition domains of the U1 and U2 splicing RNAs and acts to suppress global mRNA splicing upon SARS-CoV-2 infection. NSP1 binds to 18S ribosomal RNA in the mRNA entry channel of the ribosome and leads to global inhibition of mRNA translation upon infection. Finally, NSP8 and NSP9 bind to the 7SL RNA in the signal recognition particle and interfere with protein trafficking to the cell membrane upon infection. Disruption of each of these essential cellular functions acts to suppress the interferon response to viral infection. Our results uncover a multipronged strategy utilized by SARS-CoV-2 to antagonize essential cellular processes to suppress host defenses.
[Display omitted]
•NSP16 binds mRNA recognition domains of U1/U2 snRNAs and disrupts mRNA splicing•NSP1 binds in the mRNA entry channel of the ribosome to disrupt protein translation•NSP8 and NSP9 bind the signal recognition particle and disrupt protein trafficking•These disruptions of protein production suppress the interferon response to infection
SARS-CoV-2 proteins directly engage host RNAs to dysregulate essential steps of protein production and suppress the interferon response.</description><subject>A549 Cells</subject><subject>Animals</subject><subject>Chlorocebus aethiops</subject><subject>COVID-19 - metabolism</subject><subject>COVID-19 - virology</subject><subject>HEK293 Cells</subject><subject>Host-Pathogen Interactions</subject><subject>Humans</subject><subject>interferon</subject><subject>Interferons - metabolism</subject><subject>mRNA splicing</subject><subject>NSP1</subject><subject>NSP16</subject><subject>NSP8</subject><subject>NSP9</subject><subject>Protein Biosynthesis</subject><subject>protein trafficking</subject><subject>Protein Transport</subject><subject>RNA Splicing</subject><subject>RNA, Messenger - metabolism</subject><subject>RNA, Ribosomal, 18S - metabolism</subject><subject>RNA, Small Cytoplasmic - chemistry</subject><subject>RNA, Small Cytoplasmic - metabolism</subject><subject>RNA-protein interactions</subject><subject>SARS-CoV-2</subject><subject>SARS-CoV-2 - metabolism</subject><subject>Signal Recognition Particle - chemistry</subject><subject>Signal Recognition Particle - metabolism</subject><subject>translation</subject><subject>Vero Cells</subject><subject>Viral Nonstructural Proteins - chemistry</subject><subject>Viral Nonstructural Proteins - metabolism</subject><issn>0092-8674</issn><issn>1097-4172</issn><issn>1097-4172</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kV9rFDEUxYModq1-AR9kHn3obPNnMsmACGWrtlBQ3OqTEDLJnZp1NhmTTKHf3gxbi740L4F7f-fk5h6EXhO8Jpi0p7u1gXFcU0yXwhrj5glaEdyJuiGCPkUrjDtay1Y0R-hFSjuMseScP0dHjGGJKZEr9GN79nVbb8L3mlbnLsV5yqnaTqMzzt-cVNdR-zTq7II_qbS31ZcYMji_NIbBmV-FqnKotvM0RUipuggpV-cwgE-QXqJngx4TvLq_j9G3jx-uNxf11edPl5uzq9rwpsv10HHbCklEOZ2VhLeSMS6ssb2GrpUaelq-YqwcGPCGMhiGTmAumKBt1_fsGL0_-E5zvwdrwOeoRzVFt9fxTgXt1P8d736qm3CrBG-YlG0xeHtvEMPvGVJWe5eW5WoPYU6KNpx2ZUJMC0oPqIkhpQjDwzMEqyUWtVOLUi2xLLUSSxG9-XfAB8nfHArw7gBAWdOtg6iSceANWBfBZGWDe8z_DxEynpQ</recordid><startdate>20201125</startdate><enddate>20201125</enddate><creator>Banerjee, Abhik K.</creator><creator>Blanco, Mario R.</creator><creator>Bruce, Emily A.</creator><creator>Honson, Drew D.</creator><creator>Chen, Linlin M.</creator><creator>Chow, Amy</creator><creator>Bhat, Prashant</creator><creator>Ollikainen, Noah</creator><creator>Quinodoz, Sofia A.</creator><creator>Loney, Colin</creator><creator>Thai, Jasmine</creator><creator>Miller, Zachary D.</creator><creator>Lin, Aaron E.</creator><creator>Schmidt, Madaline M.</creator><creator>Stewart, Douglas G.</creator><creator>Goldfarb, Daniel</creator><creator>De Lorenzo, Giuditta</creator><creator>Rihn, Suzannah J.</creator><creator>Voorhees, Rebecca M.</creator><creator>Botten, Jason W.</creator><creator>Majumdar, Devdoot</creator><creator>Guttman, Mitchell</creator><general>Elsevier Inc</general><general>Cell Press</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-4654-8974</orcidid><orcidid>https://orcid.org/0000-0001-6014-387X</orcidid><orcidid>https://orcid.org/0000-0003-1862-5204</orcidid><orcidid>https://orcid.org/0000-0001-7400-4125</orcidid><orcidid>https://orcid.org/0000-0002-9797-0104</orcidid><orcidid>https://orcid.org/0000-0001-6662-6258</orcidid><orcidid>https://orcid.org/0000-0003-3893-3466</orcidid><orcidid>https://orcid.org/0000-0002-8766-2378</orcidid><orcidid>https://orcid.org/0000-0001-9495-4056</orcidid><orcidid>https://orcid.org/0000-0002-2541-3851</orcidid><orcidid>https://orcid.org/0000-0001-6839-0306</orcidid><orcidid>https://orcid.org/0000-0003-4748-9352</orcidid><orcidid>https://orcid.org/0000-0003-1640-2293</orcidid><orcidid>https://orcid.org/0000-0002-2736-8740</orcidid><orcidid>https://orcid.org/0000-0003-4503-0118</orcidid><orcidid>https://orcid.org/0000-0003-3832-4871</orcidid><orcidid>https://orcid.org/0000-0002-0508-1781</orcidid><orcidid>https://orcid.org/0000-0001-8391-370X</orcidid></search><sort><creationdate>20201125</creationdate><title>SARS-CoV-2 Disrupts Splicing, Translation, and Protein Trafficking to Suppress Host Defenses</title><author>Banerjee, Abhik K. ; 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Despite the urgent need, we still do not fully understand the molecular basis of SARS-CoV-2 pathogenesis. Here, we comprehensively define the interactions between SARS-CoV-2 proteins and human RNAs. NSP16 binds to the mRNA recognition domains of the U1 and U2 splicing RNAs and acts to suppress global mRNA splicing upon SARS-CoV-2 infection. NSP1 binds to 18S ribosomal RNA in the mRNA entry channel of the ribosome and leads to global inhibition of mRNA translation upon infection. Finally, NSP8 and NSP9 bind to the 7SL RNA in the signal recognition particle and interfere with protein trafficking to the cell membrane upon infection. Disruption of each of these essential cellular functions acts to suppress the interferon response to viral infection. Our results uncover a multipronged strategy utilized by SARS-CoV-2 to antagonize essential cellular processes to suppress host defenses.
[Display omitted]
•NSP16 binds mRNA recognition domains of U1/U2 snRNAs and disrupts mRNA splicing•NSP1 binds in the mRNA entry channel of the ribosome to disrupt protein translation•NSP8 and NSP9 bind the signal recognition particle and disrupt protein trafficking•These disruptions of protein production suppress the interferon response to infection
SARS-CoV-2 proteins directly engage host RNAs to dysregulate essential steps of protein production and suppress the interferon response.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>33080218</pmid><doi>10.1016/j.cell.2020.10.004</doi><orcidid>https://orcid.org/0000-0002-4654-8974</orcidid><orcidid>https://orcid.org/0000-0001-6014-387X</orcidid><orcidid>https://orcid.org/0000-0003-1862-5204</orcidid><orcidid>https://orcid.org/0000-0001-7400-4125</orcidid><orcidid>https://orcid.org/0000-0002-9797-0104</orcidid><orcidid>https://orcid.org/0000-0001-6662-6258</orcidid><orcidid>https://orcid.org/0000-0003-3893-3466</orcidid><orcidid>https://orcid.org/0000-0002-8766-2378</orcidid><orcidid>https://orcid.org/0000-0001-9495-4056</orcidid><orcidid>https://orcid.org/0000-0002-2541-3851</orcidid><orcidid>https://orcid.org/0000-0001-6839-0306</orcidid><orcidid>https://orcid.org/0000-0003-4748-9352</orcidid><orcidid>https://orcid.org/0000-0003-1640-2293</orcidid><orcidid>https://orcid.org/0000-0002-2736-8740</orcidid><orcidid>https://orcid.org/0000-0003-4503-0118</orcidid><orcidid>https://orcid.org/0000-0003-3832-4871</orcidid><orcidid>https://orcid.org/0000-0002-0508-1781</orcidid><orcidid>https://orcid.org/0000-0001-8391-370X</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0092-8674 |
| ispartof | Cell, 2020-11, Vol.183 (5), p.1325-1339.e21 |
| issn | 0092-8674 1097-4172 1097-4172 |
| language | eng |
| recordid | cdi_pubmed_primary_33080218 |
| source | MEDLINE; Cell Press Free Archives; Elsevier ScienceDirect Journals; EZB-FREE-00999 freely available EZB journals |
| subjects | A549 Cells Animals Chlorocebus aethiops COVID-19 - metabolism COVID-19 - virology HEK293 Cells Host-Pathogen Interactions Humans interferon Interferons - metabolism mRNA splicing NSP1 NSP16 NSP8 NSP9 Protein Biosynthesis protein trafficking Protein Transport RNA Splicing RNA, Messenger - metabolism RNA, Ribosomal, 18S - metabolism RNA, Small Cytoplasmic - chemistry RNA, Small Cytoplasmic - metabolism RNA-protein interactions SARS-CoV-2 SARS-CoV-2 - metabolism Signal Recognition Particle - chemistry Signal Recognition Particle - metabolism translation Vero Cells Viral Nonstructural Proteins - chemistry Viral Nonstructural Proteins - metabolism |
| title | SARS-CoV-2 Disrupts Splicing, Translation, and Protein Trafficking to Suppress Host Defenses |
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