A-to-I RNA editing by ADAR and its therapeutic applications: From viral infections to cancer immunotherapy.
ADAR
RNA editing
innate immunity
Journal
Wiley interdisciplinary reviews. RNA
ISSN: 1757-7012
Titre abrégé: Wiley Interdiscip Rev RNA
Pays: United States
ID NLM: 101536955
Informations de publication
Date de publication:
17 Sep 2023
17 Sep 2023
Historique:
revised:
29
08
2023
received:
11
06
2023
accepted:
29
08
2023
pmc-release:
17
03
2025
medline:
18
9
2023
pubmed:
18
9
2023
entrez:
17
9
2023
Statut:
aheadofprint
Résumé
ADAR deaminases catalyze adenosine-to-inosine (A-to-I) editing on double-stranded RNA (dsRNA) substrates that regulate an umbrella of biological processes. One of the two catalytically active ADAR enzymes, ADAR1, plays a major role in innate immune responses by suppression of RNA sensing pathways which are orchestrated through the ADAR1-dsRNA-MDA5 axis. Unedited immunogenic dsRNA substrates are potent ligands for the cellular sensor MDA5. Upon activation, MDA5 leads to the induction of interferons and expression of hundreds of interferon-stimulated genes with potent antiviral activity. In this way, ADAR1 acts as a gatekeeper of the RNA sensing pathway by striking a fine balance between innate antiviral responses and prevention of autoimmunity. Reduced editing of immunogenic dsRNA by ADAR1 is strongly linked to the development of common autoimmune and inflammatory diseases. In viral infections, ADAR1 exhibits both antiviral and proviral effects. This is modulated by both editing-dependent and editing-independent functions, such as PKR antagonism. Several A-to-I RNA editing events have been identified in viruses, including in the insidious viral pathogen, SARS-CoV-2 which regulates viral fitness and infectivity, and could play a role in shaping viral evolution. Furthermore, ADAR1 is an attractive target for immuno-oncology therapy. Overexpression of ADAR1 and increased dsRNA editing have been observed in several human cancers. Silencing ADAR1, especially in cancers that are refractory to immune checkpoint inhibitors, is a promising therapeutic strategy for cancer immunotherapy in conjunction with epigenetic therapy. The mechanistic understanding of dsRNA editing by ADAR1 and dsRNA sensing by MDA5 and PKR holds great potential for therapeutic applications. This article is categorized under: RNA Processing > RNA Editing and Modification RNA in Disease and Development > RNA in Disease.
Identifiants
pubmed: 37718249
doi: 10.1002/wrna.1817
pmc: PMC10947335
mid: NIHMS1940117
doi:
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1817Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM144100
Pays : United States
Informations de copyright
© 2023 Wiley Periodicals LLC.
Références
Annu Rev Biochem. 2010;79:321-49
pubmed: 20192758
Saudi J Biol Sci. 2021 Nov;28(11):6297-6304
pubmed: 34759749
Nucleic Acids Res. 2019 Jan 10;47(1):3-14
pubmed: 30462291
J Biol Chem. 2022 Sep;298(9):102267
pubmed: 35850307
BMJ Case Rep. 2023 Mar 13;16(3):
pubmed: 36914176
EMBO J. 1999 Jan 15;18(2):470-9
pubmed: 9889202
Sci Rep. 2019 Dec 27;9(1):19848
pubmed: 31882741
J Virol. 2007 Jan;81(2):917-23
pubmed: 17079286
Nat Rev Immunol. 2008 Jul;8(7):559-68
pubmed: 18575461
Nature. 2022 Aug;608(7923):569-577
pubmed: 35922514
Nucleic Acids Res. 2014 Jan;42(Database issue):D109-13
pubmed: 24163250
Nature. 2022 Jul;607(7920):784-789
pubmed: 35859175
Mol Cell. 2019 Mar 7;73(5):866-868
pubmed: 30849393
Immunity. 2021 Sep 14;54(9):1948-1960.e5
pubmed: 34343497
Neuropediatrics. 2016 Dec;47(6):355-360
pubmed: 27643693
Trends Microbiol. 2019 Jan;27(1):75-85
pubmed: 30201512
J Virol. 2005 May;79(10):6291-8
pubmed: 15858013
Trends Genet. 2019 Dec;35(12):903-913
pubmed: 31648814
J Biol Chem. 2019 Nov 29;294(48):18168-18180
pubmed: 31636123
Annu Rev Virol. 2021 Sep 29;8(1):239-264
pubmed: 33882257
Proc Natl Acad Sci U S A. 2011 Jan 4;108(1):331-6
pubmed: 21173229
Oncogene. 2016 Aug 18;35(33):4407-13
pubmed: 26640150
Proc Natl Acad Sci U S A. 2017 May 23;114(21):E4251-E4260
pubmed: 28484023
Gut. 2014 May;63(5):832-43
pubmed: 23766440
J Biol Chem. 2005 Apr 15;280(15):15020-8
pubmed: 15677478
Semin Immunol. 2020 Jun;49:101414
pubmed: 33011064
Immunity. 2021 Sep 14;54(9):1909-1911
pubmed: 34525334
J Virol. 2013 Jan;87(2):756-66
pubmed: 23115276
Nat Genet. 2012 Nov;44(11):1243-8
pubmed: 23001123
Mol Cell. 2023 Nov 2;83(21):3869-3884.e7
pubmed: 37797622
J Biol Chem. 2018 Oct 12;293(41):16115-16124
pubmed: 30126839
Nucleic Acids Res. 2015 Jan;43(2):1123-32
pubmed: 25564529
Genome Biol Evol. 2021 Nov 5;13(11):
pubmed: 34694399
Cell Rep. 2015 Oct 13;13(2):277-89
pubmed: 26440892
Clin Microbiol Rev. 2009 Apr;22(2):240-73, Table of Contents
pubmed: 19366914
Nat Rev Genet. 2022 Oct;23(10):581
pubmed: 35922480
Science. 1999 Jun 11;284(5421):1841-5
pubmed: 10364558
Genome Biol. 2012 Dec 28;13(12):252
pubmed: 23273215
Annu Rev Biochem. 2002;71:817-46
pubmed: 12045112
Nat Rev Immunol. 2016 Sep;16(9):566-80
pubmed: 27455396
Nat Commun. 2018 Dec 21;9(1):5450
pubmed: 30575730
J Biol Chem. 2004 Feb 6;279(6):4952-61
pubmed: 14613934
Cell Rep. 2021 Oct 19;37(3):109858
pubmed: 34686350
Nat Immunol. 2009 Jan;10(1):109-15
pubmed: 19060901
PLoS Biol. 2018 Nov 29;16(11):e2006577
pubmed: 30496178
Nucleic Acids Res. 2013 Nov;41(21):9786-99
pubmed: 23982513
Cancer Cell. 2015 Oct 12;28(4):515-528
pubmed: 26439496
Nat Biotechnol. 2004 Aug;22(8):1001-5
pubmed: 15258596
Nat Commun. 2022 Apr 4;13(1):1804
pubmed: 35379808
Science. 2000 Dec 1;290(5497):1765-8
pubmed: 11099415
Cell. 1989 Feb 10;56(3):331
pubmed: 2914324
Cell Rep. 2014 Nov 20;9(4):1482-94
pubmed: 25456137
Curr Top Microbiol Immunol. 2012;353:163-95
pubmed: 21809195
PLoS Biol. 2004 Dec;2(12):e391
pubmed: 15534692
Nat Rev Immunol. 2022 Sep;22(9):531
pubmed: 35931817
Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):15118-23
pubmed: 12399548
Nat Rev Cancer. 2017 Jun;17(6):381-392
pubmed: 28416802
Trends Biochem Sci. 2021 Sep;46(9):758-771
pubmed: 33736931
J Virol. 2010 Nov;84(22):11898-904
pubmed: 20844035
Cell Rep. 2019 Feb 19;26(8):2019-2027.e4
pubmed: 30784585
NAR Cancer. 2023 Jun 01;5(2):zcad023
pubmed: 37275274
Nature. 2022 Jul;607(7920):769-775
pubmed: 35859177
Virology. 2015 Nov;485:475-80
pubmed: 26363218
Oncogene. 2021 Jan;40(1):189-202
pubmed: 33110236
Proc Natl Acad Sci U S A. 2021 Mar 23;118(12):
pubmed: 33723056
Nat Rev Rheumatol. 2022 Dec;18(12):681-682
pubmed: 36203062
PLoS Pathog. 2020 Sep 8;16(9):e1008842
pubmed: 32898178
Nat Genet. 2014 May;46(5):503-509
pubmed: 24686847
Immunity. 2015 Nov 17;43(5):933-44
pubmed: 26588779
Tumour Biol. 2017 Oct;39(10):1010428317734816
pubmed: 29022489
Nucleic Acids Res. 2020 Nov 18;48(20):11664-11674
pubmed: 33137199
Genome Res. 2004 Dec;14(12):2379-87
pubmed: 15545495
Bioessays. 2017 Apr;39(4):
pubmed: 28217931
J Biol Chem. 2020 Jun 12;295(24):8325-8330
pubmed: 32350114
Adv Exp Med Biol. 2011;700:76-84
pubmed: 21755475
Nat Rev Genet. 2018 Aug;19(8):473-490
pubmed: 29692414
Mol Cancer. 2021 Mar 9;20(1):51
pubmed: 33750389
Proc Natl Acad Sci U S A. 2022 Feb 8;119(6):
pubmed: 35064076
Cancer Res Commun. 2021 Nov;1(2):56-64
pubmed: 35586115
Nucleic Acids Res. 2023 May 22;51(9):4191-4207
pubmed: 37026479
Hum Mutat. 2020 Apr;41(4):837-849
pubmed: 31898846
Nucleic Acids Res. 2022 Mar 21;50(5):2509-2521
pubmed: 35234938
Nature. 2019 Jan;565(7737):43-48
pubmed: 30559380
Nature. 2017 Jul 27;547(7664):413-418
pubmed: 28723893
Proc Natl Acad Sci U S A. 2016 Feb 23;113(8):2241-6
pubmed: 26858407
Cell Rep. 2021 Aug 10;36(6):109500
pubmed: 34380029
Nat Rev Genet. 2008 Apr;9(4):267-76
pubmed: 18319742
Curr Top Microbiol Immunol. 2012;353:35-60
pubmed: 21728134
Genes (Basel). 2021 Dec 23;13(1):
pubmed: 35052382
Nat Methods. 2012 Jun;9(6):579-81
pubmed: 22484847
Wiley Interdiscip Rev RNA. 2016 Mar-Apr;7(2):157-72
pubmed: 26692549
Nat Rev Mol Cell Biol. 2016 Feb;17(2):83-96
pubmed: 26648264
Trends Genet. 2022 Aug;38(8):821-830
pubmed: 35459560
EBioMedicine. 2018 Jan;27:167-175
pubmed: 29273356
EMBO J. 2008 Jun 18;27(12):1694-705
pubmed: 18497743
J Virol. 2002 Apr;76(8):3819-27
pubmed: 11907222
Sci Signal. 2017 Sep 19;10(497):
pubmed: 28928239
Neuropediatrics. 2017 Jun;48(3):166-184
pubmed: 28561207
Immunity. 2021 Sep 14;54(9):1961-1975.e5
pubmed: 34525337
Mol Cell Biol. 1995 Oct;15(10):5376-88
pubmed: 7565688
Nature. 2017 Oct 11;550(7675):249-254
pubmed: 29022589
Nat Commun. 2017 Nov 13;8(1):1440
pubmed: 29129909
Front Endocrinol (Lausanne). 2018 Dec 18;9:762
pubmed: 30619092
Cell Rep. 2015 Oct 13;13(2):267-76
pubmed: 26440895
Science. 2006 Nov 10;314(5801):997-1001
pubmed: 17038589
Mol Biol Cell. 2002 Nov;13(11):3822-35
pubmed: 12429827
Crit Rev Biochem Mol Biol. 2021 Feb;56(1):54-87
pubmed: 33356612
Am J Hum Genet. 2015 Feb 5;96(2):275-82
pubmed: 25620204
J Biol Chem. 2009 Oct 23;284(43):29350-6
pubmed: 19710021
J Virol. 2012 Apr;86(7):3787-94
pubmed: 22278222
Cell. 2015 Aug 27;162(5):961-73
pubmed: 26317465
Trends Immunol. 2021 Nov;42(11):953-955
pubmed: 34642093
J Eur Acad Dermatol Venereol. 2022 Jan;36(1):e54-e57
pubmed: 34418169
Virology. 2011 Mar 15;411(2):180-93
pubmed: 21211811
Wiley Interdiscip Rev Syst Biol Med. 2009 Sep-Oct;1(2):202-209
pubmed: 20835992
Am J Cancer Res. 2020 Jan 01;10(1):148-163
pubmed: 32064158
Nature. 2020 Oct;586(7827):120-126
pubmed: 32968282
J Virol. 2004 Dec;78(23):12747-61
pubmed: 15542627
Wiley Interdiscip Rev RNA. 2022 Jan;13(1):e1665
pubmed: 34105255
J Gen Virol. 2016 Nov;97(11):2973-2988
pubmed: 27655063
Proc Natl Acad Sci U S A. 1997 Aug 5;94(16):8421-6
pubmed: 9237992
Nucleic Acids Res. 2019 Feb 28;47(4):e22
pubmed: 30590609
Genome Biol. 2017 Oct 30;18(1):205
pubmed: 29084589
Proc Natl Acad Sci U S A. 2001 Oct 9;98(21):12132-7
pubmed: 11593027
J Virol. 2020 Nov 9;94(23):
pubmed: 32938769
Curr Opin Virol. 2015 Jun;12:20-5
pubmed: 25676875
Cell. 2018 Feb 8;172(4):797-810.e13
pubmed: 29395326
Science. 2015 Sep 4;349(6252):1115-20
pubmed: 26275108
Nat Med. 2019 Jan;25(1):95-102
pubmed: 30559422
J Interferon Cytokine Res. 2011 Jan;31(1):99-117
pubmed: 21182352
Arthritis Rheumatol. 2015 Jun;67(6):1592-7
pubmed: 25777993
Nature. 2020 Dec;588(7836):169-173
pubmed: 33087935
RNA. 2000 May;6(5):755-67
pubmed: 10836796
Structure. 2007 Apr;15(4):395-404
pubmed: 17437712
Cell. 2018 Feb 8;172(4):811-824.e14
pubmed: 29395325
Nature. 2006 May 4;441(7089):101-5
pubmed: 16625202
Nat Commun. 2017 Dec 4;8(1):1922
pubmed: 29203771
Nat Med. 2013 Feb;19(2):209-16
pubmed: 23291631
Methods Mol Biol. 2023;2651:285-294
pubmed: 36892775
Proc Natl Acad Sci U S A. 2012 Dec 4;109(49):E3340-9
pubmed: 23129641
Wiley Interdiscip Rev RNA. 2019 Jul;10(4):e1534
pubmed: 30989826
Genome Biol. 2017 Sep 5;18(1):166
pubmed: 28874170
J Transl Med. 2019 Sep 23;17(1):319
pubmed: 31547885
PLoS Genet. 2022 Mar 30;18(3):e1010130
pubmed: 35353808
J Biol Chem. 2019 Feb 1;294(5):1710-1720
pubmed: 30710018
Cell Rep. 2021 Jan 12;34(2):108628
pubmed: 33440148
Nucleic Acids Res. 2014 Jun;42(11):6876-84
pubmed: 24829451
Nature. 2022 Jun;606(7914):594-602
pubmed: 35614224
Sci Adv. 2020 Jun 17;6(25):eabb5813
pubmed: 32596474
Nucleic Acids Res. 2005 Sep 21;33(16):5362-70
pubmed: 16177183
J Virol. 2009 Oct;83(19):10119-28
pubmed: 19605474
Nature. 2022 Jul;607(7920):776-783
pubmed: 35859176
Immunity. 2021 Sep 14;54(9):1976-1988.e7
pubmed: 34525338
Cell. 2015 Aug 27;162(5):974-86
pubmed: 26317466
Nature. 1996 Apr 4;380(6573):454-6
pubmed: 8602246
Trends Pharmacol Sci. 2019 Feb;40(2):116-127
pubmed: 30606502
Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3542-7
pubmed: 9108012