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ADAR RNA Modifications, the Epitranscriptome and Innate Immunity
Modified bases act as marks on cellular RNAs so that they can be distinguished from foreign RNAs, reducing innate immune responses to endogenous RNA. In humans, mutations giving reduced levels of one base modification, adenosine-to-inosine deamination, cause a viral infection mimic syndrome, a conge...
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| Published in: | Trends in biochemical sciences (Amsterdam. Regular ed.) 2021-09, Vol.46 (9), p.758-771 |
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| container_title | Trends in biochemical sciences (Amsterdam. Regular ed.) |
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| creator | Quin, Jaclyn Sedmík, Jiří Vukić, Dragana Khan, Anzer Keegan, Liam P. O’Connell, Mary A. |
| description | Modified bases act as marks on cellular RNAs so that they can be distinguished from foreign RNAs, reducing innate immune responses to endogenous RNA. In humans, mutations giving reduced levels of one base modification, adenosine-to-inosine deamination, cause a viral infection mimic syndrome, a congenital encephalitis with aberrant interferon induction. These Aicardi-Goutières syndrome 6 mutations affect adenosine deaminase acting on RNA 1 (ADAR1), which generates inosines in endogenous double-stranded (ds)RNA. The inosine base alters dsRNA structure to prevent aberrant activation of antiviral cytosolic helicase RIG-I–like receptors. We review how effects of inosines, ADARs, and other modified bases have been shown to be important in innate immunity and cancer.
Epitranscriptomic RNA modifications act as marks of innate immune self in RNA; they are critical in current mRNA vaccines.Studies on adenosine-to-inosine deamination by ADAR enzymes show how inosine acts as a mark of self-RNA by altering the structure of double-stranded (ds)RNA to prevent aberrant activation of antiviral RIG-I–like receptors (RLRs).Self-marks in RNA threshold and balance innate immune defences against infections; ADAR mutations cause inflammatory diseases.Helicase domains of RLRs scan along perfect dsRNA, and RLRs form signalling complexes cooperatively; base mismatches or I-U base pairs cause RLR disassociation from RNA, and the ancestral helicase domains of DICER proteins probably originated this mechanism.Knockdown of ADAR1, and potentially also small molecule inhibitors of ADAR1, kill some cancer cells directly and strongly enhance killing of others by immune checkpoint blockade. |
| doi_str_mv | 10.1016/j.tibs.2021.02.002 |
| format | article |
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Epitranscriptomic RNA modifications act as marks of innate immune self in RNA; they are critical in current mRNA vaccines.Studies on adenosine-to-inosine deamination by ADAR enzymes show how inosine acts as a mark of self-RNA by altering the structure of double-stranded (ds)RNA to prevent aberrant activation of antiviral RIG-I–like receptors (RLRs).Self-marks in RNA threshold and balance innate immune defences against infections; ADAR mutations cause inflammatory diseases.Helicase domains of RLRs scan along perfect dsRNA, and RLRs form signalling complexes cooperatively; base mismatches or I-U base pairs cause RLR disassociation from RNA, and the ancestral helicase domains of DICER proteins probably originated this mechanism.Knockdown of ADAR1, and potentially also small molecule inhibitors of ADAR1, kill some cancer cells directly and strongly enhance killing of others by immune checkpoint blockade.</description><identifier>ISSN: 0968-0004</identifier><identifier>EISSN: 1362-4326</identifier><identifier>DOI: 10.1016/j.tibs.2021.02.002</identifier><identifier>PMID: 33736931</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Adenosine Deaminase - genetics ; Adenosine Deaminase - metabolism ; antiviral responses ; autoinflammatory disease ; double-stranded RNA (dsRNA) ; Humans ; Immunity, Innate ; interferon ; pattern recognition receptors (PRRs) ; RNA Editing ; RNA, Double-Stranded ; RNA-Binding Proteins - metabolism ; Transcriptome</subject><ispartof>Trends in biochemical sciences (Amsterdam. Regular ed.), 2021-09, Vol.46 (9), p.758-771</ispartof><rights>2021 The Authors</rights><rights>Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c428t-e52e8a591e07650abf57d44e34c3d858ef8ffe771bc8ad12add81658099851c43</citedby><cites>FETCH-LOGICAL-c428t-e52e8a591e07650abf57d44e34c3d858ef8ffe771bc8ad12add81658099851c43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33736931$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Quin, Jaclyn</creatorcontrib><creatorcontrib>Sedmík, Jiří</creatorcontrib><creatorcontrib>Vukić, Dragana</creatorcontrib><creatorcontrib>Khan, Anzer</creatorcontrib><creatorcontrib>Keegan, Liam P.</creatorcontrib><creatorcontrib>O’Connell, Mary A.</creatorcontrib><title>ADAR RNA Modifications, the Epitranscriptome and Innate Immunity</title><title>Trends in biochemical sciences (Amsterdam. Regular ed.)</title><addtitle>Trends Biochem Sci</addtitle><description>Modified bases act as marks on cellular RNAs so that they can be distinguished from foreign RNAs, reducing innate immune responses to endogenous RNA. In humans, mutations giving reduced levels of one base modification, adenosine-to-inosine deamination, cause a viral infection mimic syndrome, a congenital encephalitis with aberrant interferon induction. These Aicardi-Goutières syndrome 6 mutations affect adenosine deaminase acting on RNA 1 (ADAR1), which generates inosines in endogenous double-stranded (ds)RNA. The inosine base alters dsRNA structure to prevent aberrant activation of antiviral cytosolic helicase RIG-I–like receptors. We review how effects of inosines, ADARs, and other modified bases have been shown to be important in innate immunity and cancer.
Epitranscriptomic RNA modifications act as marks of innate immune self in RNA; they are critical in current mRNA vaccines.Studies on adenosine-to-inosine deamination by ADAR enzymes show how inosine acts as a mark of self-RNA by altering the structure of double-stranded (ds)RNA to prevent aberrant activation of antiviral RIG-I–like receptors (RLRs).Self-marks in RNA threshold and balance innate immune defences against infections; ADAR mutations cause inflammatory diseases.Helicase domains of RLRs scan along perfect dsRNA, and RLRs form signalling complexes cooperatively; base mismatches or I-U base pairs cause RLR disassociation from RNA, and the ancestral helicase domains of DICER proteins probably originated this mechanism.Knockdown of ADAR1, and potentially also small molecule inhibitors of ADAR1, kill some cancer cells directly and strongly enhance killing of others by immune checkpoint blockade.</description><subject>Adenosine Deaminase - genetics</subject><subject>Adenosine Deaminase - metabolism</subject><subject>antiviral responses</subject><subject>autoinflammatory disease</subject><subject>double-stranded RNA (dsRNA)</subject><subject>Humans</subject><subject>Immunity, Innate</subject><subject>interferon</subject><subject>pattern recognition receptors (PRRs)</subject><subject>RNA Editing</subject><subject>RNA, Double-Stranded</subject><subject>RNA-Binding Proteins - metabolism</subject><subject>Transcriptome</subject><issn>0968-0004</issn><issn>1362-4326</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp9kE9LwzAYh4Mobv75Ah6kRw-2vkmaNgUPjjl1MBWGnkOWvMWMtZ1JJuzb2zH16Om9PL8H3oeQCwoZBVrcLLPoFiFjwGgGLANgB2RIecHSnLPikAyhKmQKAPmAnISwBKCiLMUxGXBe8qLidEjuRvejeTJ_GSXPnXW1Mzq6rg3XSfzAZLJ20es2GO_WsWsw0a1Npm2rIybTptm0Lm7PyFGtVwHPf-4peX-YvI2f0tnr43Q8mqUmZzKmKBhKLSqKUBYC9KIWpc1z5LnhVgqJtaxrLEu6MFJbyrS1khZCQlVJQU3OT8nV3rv23ecGQ1SNCwZXK91itwmKCeAFh7wqe5TtUeO7EDzWau1do_1WUVC7cmqpduXUrpwCpvpy_ejyx79ZNGj_Jr-peuB2D2D_5ZdDr4Jx2Bq0zqOJynbuP_83x8V92w</recordid><startdate>202109</startdate><enddate>202109</enddate><creator>Quin, Jaclyn</creator><creator>Sedmík, Jiří</creator><creator>Vukić, Dragana</creator><creator>Khan, Anzer</creator><creator>Keegan, Liam P.</creator><creator>O’Connell, Mary A.</creator><general>Elsevier Ltd</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></search><sort><creationdate>202109</creationdate><title>ADAR RNA Modifications, the Epitranscriptome and Innate Immunity</title><author>Quin, Jaclyn ; Sedmík, Jiří ; Vukić, Dragana ; Khan, Anzer ; Keegan, Liam P. ; O’Connell, Mary A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c428t-e52e8a591e07650abf57d44e34c3d858ef8ffe771bc8ad12add81658099851c43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adenosine Deaminase - genetics</topic><topic>Adenosine Deaminase - metabolism</topic><topic>antiviral responses</topic><topic>autoinflammatory disease</topic><topic>double-stranded RNA (dsRNA)</topic><topic>Humans</topic><topic>Immunity, Innate</topic><topic>interferon</topic><topic>pattern recognition receptors (PRRs)</topic><topic>RNA Editing</topic><topic>RNA, Double-Stranded</topic><topic>RNA-Binding Proteins - metabolism</topic><topic>Transcriptome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Quin, Jaclyn</creatorcontrib><creatorcontrib>Sedmík, Jiří</creatorcontrib><creatorcontrib>Vukić, Dragana</creatorcontrib><creatorcontrib>Khan, Anzer</creatorcontrib><creatorcontrib>Keegan, Liam P.</creatorcontrib><creatorcontrib>O’Connell, Mary A.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</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><jtitle>Trends in biochemical sciences (Amsterdam. Regular ed.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Quin, Jaclyn</au><au>Sedmík, Jiří</au><au>Vukić, Dragana</au><au>Khan, Anzer</au><au>Keegan, Liam P.</au><au>O’Connell, Mary A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>ADAR RNA Modifications, the Epitranscriptome and Innate Immunity</atitle><jtitle>Trends in biochemical sciences (Amsterdam. Regular ed.)</jtitle><addtitle>Trends Biochem Sci</addtitle><date>2021-09</date><risdate>2021</risdate><volume>46</volume><issue>9</issue><spage>758</spage><epage>771</epage><pages>758-771</pages><issn>0968-0004</issn><eissn>1362-4326</eissn><notes>ObjectType-Article-2</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-3</notes><notes>content type line 23</notes><notes>ObjectType-Review-1</notes><abstract>Modified bases act as marks on cellular RNAs so that they can be distinguished from foreign RNAs, reducing innate immune responses to endogenous RNA. In humans, mutations giving reduced levels of one base modification, adenosine-to-inosine deamination, cause a viral infection mimic syndrome, a congenital encephalitis with aberrant interferon induction. These Aicardi-Goutières syndrome 6 mutations affect adenosine deaminase acting on RNA 1 (ADAR1), which generates inosines in endogenous double-stranded (ds)RNA. The inosine base alters dsRNA structure to prevent aberrant activation of antiviral cytosolic helicase RIG-I–like receptors. We review how effects of inosines, ADARs, and other modified bases have been shown to be important in innate immunity and cancer.
Epitranscriptomic RNA modifications act as marks of innate immune self in RNA; they are critical in current mRNA vaccines.Studies on adenosine-to-inosine deamination by ADAR enzymes show how inosine acts as a mark of self-RNA by altering the structure of double-stranded (ds)RNA to prevent aberrant activation of antiviral RIG-I–like receptors (RLRs).Self-marks in RNA threshold and balance innate immune defences against infections; ADAR mutations cause inflammatory diseases.Helicase domains of RLRs scan along perfect dsRNA, and RLRs form signalling complexes cooperatively; base mismatches or I-U base pairs cause RLR disassociation from RNA, and the ancestral helicase domains of DICER proteins probably originated this mechanism.Knockdown of ADAR1, and potentially also small molecule inhibitors of ADAR1, kill some cancer cells directly and strongly enhance killing of others by immune checkpoint blockade.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>33736931</pmid><doi>10.1016/j.tibs.2021.02.002</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adenosine Deaminase - genetics Adenosine Deaminase - metabolism antiviral responses autoinflammatory disease double-stranded RNA (dsRNA) Humans Immunity, Innate interferon pattern recognition receptors (PRRs) RNA Editing RNA, Double-Stranded RNA-Binding Proteins - metabolism Transcriptome |
| title | ADAR RNA Modifications, the Epitranscriptome and Innate Immunity |
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