The RNA binding protein Quaking represses splicing of the Fibronectin EDA exon and downregulates the interferon response
Abstract Quaking (QKI) controls RNA metabolism in many biological processes including innate immunity, where its roles remain incompletely understood. To illuminate these roles, we performed genome scale transcriptome profiling in QKI knockout cells with or without poly(I:C) transfection, a double-s...
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| Veröffentlicht in: | Nucleic acids research 2021-09, Vol.49 (17), p.10034-10045 |
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| creator | Liao, Kuo-Chieh Chuo, Vanessa Fagg, W Samuel Modahl, Cassandra M Widen, Steven Garcia-Blanco, Mariano A |
| description | Abstract
Quaking (QKI) controls RNA metabolism in many biological processes including innate immunity, where its roles remain incompletely understood. To illuminate these roles, we performed genome scale transcriptome profiling in QKI knockout cells with or without poly(I:C) transfection, a double-stranded RNA analog that mimics viral infection. Analysis of RNA-sequencing data shows that QKI knockout upregulates genes induced by interferons, suggesting that QKI is an immune suppressor. Furthermore, differential splicing analysis shows that QKI primarily controls cassette exons, and among these events, we noted that QKI silences splicing of the extra domain A (EDA) exon in fibronectin (FN1) transcripts. QKI knockout results in elevated production and secretion of FN1-EDA protein, which is a known activator of interferons. Consistent with an upregulation of the interferon response in QKI knockout cells, our results show reduced production of dengue virus-2 and Japanese encephalitis virus in these cells. In conclusion, we demonstrate that QKI downregulates the interferon system and attenuates the antiviral state. |
| doi_str_mv | 10.1093/nar/gkab732 |
| format | Article |
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Quaking (QKI) controls RNA metabolism in many biological processes including innate immunity, where its roles remain incompletely understood. To illuminate these roles, we performed genome scale transcriptome profiling in QKI knockout cells with or without poly(I:C) transfection, a double-stranded RNA analog that mimics viral infection. Analysis of RNA-sequencing data shows that QKI knockout upregulates genes induced by interferons, suggesting that QKI is an immune suppressor. Furthermore, differential splicing analysis shows that QKI primarily controls cassette exons, and among these events, we noted that QKI silences splicing of the extra domain A (EDA) exon in fibronectin (FN1) transcripts. QKI knockout results in elevated production and secretion of FN1-EDA protein, which is a known activator of interferons. Consistent with an upregulation of the interferon response in QKI knockout cells, our results show reduced production of dengue virus-2 and Japanese encephalitis virus in these cells. In conclusion, we demonstrate that QKI downregulates the interferon system and attenuates the antiviral state.</description><identifier>ISSN: 0305-1048</identifier><identifier>EISSN: 1362-4962</identifier><identifier>DOI: 10.1093/nar/gkab732</identifier><identifier>PMID: 34428287</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>A549 Cells ; Cell Line, Tumor ; Dengue Virus - growth & development ; Dengue Virus - immunology ; Encephalitis Virus, Japanese - growth & development ; Encephalitis Virus, Japanese - immunology ; Fibronectins - genetics ; Gene Expression Profiling ; Humans ; Immunity, Innate - genetics ; Immunity, Innate - immunology ; Interferon Type I - genetics ; Interferon Type I - immunology ; Poly I-C - immunology ; RNA and RNA-protein complexes ; RNA Interference ; RNA Splicing - genetics ; RNA, Small Interfering - genetics ; RNA-Binding Proteins - genetics ; RNA-Binding Proteins - metabolism ; Transcriptome - genetics ; Up-Regulation - genetics</subject><ispartof>Nucleic acids research, 2021-09, Vol.49 (17), p.10034-10045</ispartof><rights>The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research. 2021</rights><rights>The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c412t-a6f80569f1bc38d51f5731c011a698a18a4f5c6f934cded2be30f395a6c99823</citedby><cites>FETCH-LOGICAL-c412t-a6f80569f1bc38d51f5731c011a698a18a4f5c6f934cded2be30f395a6c99823</cites><orcidid>0000-0001-8538-1997 ; 0000-0003-2909-1666 ; 0000-0002-8766-4824</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8464043/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8464043/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,1604,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34428287$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liao, Kuo-Chieh</creatorcontrib><creatorcontrib>Chuo, Vanessa</creatorcontrib><creatorcontrib>Fagg, W Samuel</creatorcontrib><creatorcontrib>Modahl, Cassandra M</creatorcontrib><creatorcontrib>Widen, Steven</creatorcontrib><creatorcontrib>Garcia-Blanco, Mariano A</creatorcontrib><title>The RNA binding protein Quaking represses splicing of the Fibronectin EDA exon and downregulates the interferon response</title><title>Nucleic acids research</title><addtitle>Nucleic Acids Res</addtitle><description>Abstract
Quaking (QKI) controls RNA metabolism in many biological processes including innate immunity, where its roles remain incompletely understood. To illuminate these roles, we performed genome scale transcriptome profiling in QKI knockout cells with or without poly(I:C) transfection, a double-stranded RNA analog that mimics viral infection. Analysis of RNA-sequencing data shows that QKI knockout upregulates genes induced by interferons, suggesting that QKI is an immune suppressor. Furthermore, differential splicing analysis shows that QKI primarily controls cassette exons, and among these events, we noted that QKI silences splicing of the extra domain A (EDA) exon in fibronectin (FN1) transcripts. QKI knockout results in elevated production and secretion of FN1-EDA protein, which is a known activator of interferons. Consistent with an upregulation of the interferon response in QKI knockout cells, our results show reduced production of dengue virus-2 and Japanese encephalitis virus in these cells. In conclusion, we demonstrate that QKI downregulates the interferon system and attenuates the antiviral state.</description><subject>A549 Cells</subject><subject>Cell Line, Tumor</subject><subject>Dengue Virus - growth & development</subject><subject>Dengue Virus - immunology</subject><subject>Encephalitis Virus, Japanese - growth & development</subject><subject>Encephalitis Virus, Japanese - immunology</subject><subject>Fibronectins - genetics</subject><subject>Gene Expression Profiling</subject><subject>Humans</subject><subject>Immunity, Innate - genetics</subject><subject>Immunity, Innate - immunology</subject><subject>Interferon Type I - genetics</subject><subject>Interferon Type I - immunology</subject><subject>Poly I-C - immunology</subject><subject>RNA and RNA-protein complexes</subject><subject>RNA Interference</subject><subject>RNA Splicing - genetics</subject><subject>RNA, Small Interfering - genetics</subject><subject>RNA-Binding Proteins - genetics</subject><subject>RNA-Binding Proteins - metabolism</subject><subject>Transcriptome - genetics</subject><subject>Up-Regulation - genetics</subject><issn>0305-1048</issn><issn>1362-4962</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>TOX</sourceid><sourceid>EIF</sourceid><recordid>eNp9kc1rFDEYh4NY7Fo9eZecRCjT5muyyUVY-qFCUZS9h0zmzTZ2NhmTGdv-92bZtejFU0jy_J73hR9Cbyg5o0Tz82jz-ebOdkvOnqEF5ZI1Qkv2HC0IJ21DiVDH6GUpPwihgrbiBTrmQjDF1HKBHta3gL9_WeEuxD7EDR5zmiBE_G22d7t7hjFDKVBwGYfgdk_J46mmrkOXUwQ3VfrqcoXhIUVsY4_7dB8zbObBTjW2Q0OcIHuoePWVMcUCr9CRt0OB14fzBK2vr9YXn5qbrx8_X6xuGicomxorvSKt1J52jqu-pb5dcuoIpVZqZamywrdOes2F66FnHXDiuW6tdForxk_Qh712nLst9A7ilO1gxhy2Nj-aZIP59yeGW7NJv4wSUhDBq-D9QZDTzxnKZLahOBgGGyHNxbBWCqEFkcuKnu5Rl1MpGfzTGErMripTqzKHqir99u_Nntg_3VTg3R5I8_hf02-gCqBh</recordid><startdate>20210927</startdate><enddate>20210927</enddate><creator>Liao, Kuo-Chieh</creator><creator>Chuo, Vanessa</creator><creator>Fagg, W Samuel</creator><creator>Modahl, Cassandra M</creator><creator>Widen, Steven</creator><creator>Garcia-Blanco, Mariano A</creator><general>Oxford University Press</general><scope>TOX</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/0000-0001-8538-1997</orcidid><orcidid>https://orcid.org/0000-0003-2909-1666</orcidid><orcidid>https://orcid.org/0000-0002-8766-4824</orcidid></search><sort><creationdate>20210927</creationdate><title>The RNA binding protein Quaking represses splicing of the Fibronectin EDA exon and downregulates the interferon response</title><author>Liao, Kuo-Chieh ; Chuo, Vanessa ; Fagg, W Samuel ; Modahl, Cassandra M ; Widen, Steven ; Garcia-Blanco, Mariano A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c412t-a6f80569f1bc38d51f5731c011a698a18a4f5c6f934cded2be30f395a6c99823</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>A549 Cells</topic><topic>Cell Line, Tumor</topic><topic>Dengue Virus - growth & development</topic><topic>Dengue Virus - immunology</topic><topic>Encephalitis Virus, Japanese - growth & development</topic><topic>Encephalitis Virus, Japanese - immunology</topic><topic>Fibronectins - genetics</topic><topic>Gene Expression Profiling</topic><topic>Humans</topic><topic>Immunity, Innate - genetics</topic><topic>Immunity, Innate - immunology</topic><topic>Interferon Type I - genetics</topic><topic>Interferon Type I - immunology</topic><topic>Poly I-C - immunology</topic><topic>RNA and RNA-protein complexes</topic><topic>RNA Interference</topic><topic>RNA Splicing - genetics</topic><topic>RNA, Small Interfering - genetics</topic><topic>RNA-Binding Proteins - genetics</topic><topic>RNA-Binding Proteins - metabolism</topic><topic>Transcriptome - genetics</topic><topic>Up-Regulation - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liao, Kuo-Chieh</creatorcontrib><creatorcontrib>Chuo, Vanessa</creatorcontrib><creatorcontrib>Fagg, W Samuel</creatorcontrib><creatorcontrib>Modahl, Cassandra M</creatorcontrib><creatorcontrib>Widen, Steven</creatorcontrib><creatorcontrib>Garcia-Blanco, Mariano A</creatorcontrib><collection>Oxford Journals Open Access Collection</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nucleic acids research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liao, Kuo-Chieh</au><au>Chuo, Vanessa</au><au>Fagg, W Samuel</au><au>Modahl, Cassandra M</au><au>Widen, Steven</au><au>Garcia-Blanco, Mariano A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The RNA binding protein Quaking represses splicing of the Fibronectin EDA exon and downregulates the interferon response</atitle><jtitle>Nucleic acids research</jtitle><addtitle>Nucleic Acids Res</addtitle><date>2021-09-27</date><risdate>2021</risdate><volume>49</volume><issue>17</issue><spage>10034</spage><epage>10045</epage><pages>10034-10045</pages><issn>0305-1048</issn><eissn>1362-4962</eissn><abstract>Abstract
Quaking (QKI) controls RNA metabolism in many biological processes including innate immunity, where its roles remain incompletely understood. To illuminate these roles, we performed genome scale transcriptome profiling in QKI knockout cells with or without poly(I:C) transfection, a double-stranded RNA analog that mimics viral infection. Analysis of RNA-sequencing data shows that QKI knockout upregulates genes induced by interferons, suggesting that QKI is an immune suppressor. Furthermore, differential splicing analysis shows that QKI primarily controls cassette exons, and among these events, we noted that QKI silences splicing of the extra domain A (EDA) exon in fibronectin (FN1) transcripts. QKI knockout results in elevated production and secretion of FN1-EDA protein, which is a known activator of interferons. Consistent with an upregulation of the interferon response in QKI knockout cells, our results show reduced production of dengue virus-2 and Japanese encephalitis virus in these cells. In conclusion, we demonstrate that QKI downregulates the interferon system and attenuates the antiviral state.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>34428287</pmid><doi>10.1093/nar/gkab732</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0001-8538-1997</orcidid><orcidid>https://orcid.org/0000-0003-2909-1666</orcidid><orcidid>https://orcid.org/0000-0002-8766-4824</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | A549 Cells Cell Line, Tumor Dengue Virus - growth & development Dengue Virus - immunology Encephalitis Virus, Japanese - growth & development Encephalitis Virus, Japanese - immunology Fibronectins - genetics Gene Expression Profiling Humans Immunity, Innate - genetics Immunity, Innate - immunology Interferon Type I - genetics Interferon Type I - immunology Poly I-C - immunology RNA and RNA-protein complexes RNA Interference RNA Splicing - genetics RNA, Small Interfering - genetics RNA-Binding Proteins - genetics RNA-Binding Proteins - metabolism Transcriptome - genetics Up-Regulation - genetics |
| title | The RNA binding protein Quaking represses splicing of the Fibronectin EDA exon and downregulates the interferon response |
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