A loosened gating mechanism of RIG-I leads to autoimmune disorders.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
10 06 2022
10 06 2022
Historique:
accepted:
27
04
2022
revised:
22
04
2022
received:
22
02
2022
pubmed:
18
5
2022
medline:
11
6
2022
entrez:
17
5
2022
Statut:
ppublish
Résumé
DDX58 encodes RIG-I, a cytosolic RNA sensor that ensures immune surveillance of nonself RNAs. Individuals with RIG-IE510V and RIG-IQ517H mutations have increased susceptibility to Singleton-Merten syndrome (SMS) defects, resulting in tissue-specific (mild) and classic (severe) phenotypes. The coupling between RNA recognition and conformational changes is central to RIG-I RNA proofreading, but the molecular determinants leading to dissociated disease phenotypes remain unknown. Herein, we employed hydrogen/deuterium exchange mass spectrometry (HDX-MS) and single molecule magnetic tweezers (MT) to precisely examine how subtle conformational changes in the helicase insertion domain (HEL2i) promote impaired ATPase and erroneous RNA proofreading activities. We showed that the mutations cause a loosened latch-gate engagement in apo RIG-I, which in turn gradually dampens its self RNA (Cap2 moiety:m7G cap and N1-2-2'-O-methylation RNA) proofreading ability, leading to increased immunopathy. These results reveal HEL2i as a unique checkpoint directing two specialized functions, i.e. stabilizing the CARD2-HEL2i interface and gating the helicase from incoming self RNAs; thus, these findings add new insights into the role of HEL2i in the control of antiviral innate immunity and autoimmunity diseases.
Identifiants
pubmed: 35580046
pii: 6586872
doi: 10.1093/nar/gkac361
pmc: PMC9177982
doi:
Substances chimiques
RNA
63231-63-0
DEAD Box Protein 58
EC 3.6.4.13
DEAD-box RNA Helicases
EC 3.6.4.13
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5850-5863Informations de copyright
© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.
Références
Curr Opin Struct Biol. 2010 Jun;20(3):313-24
pubmed: 20456941
J Am Soc Mass Spectrom. 2012 Sep;23(9):1512-21
pubmed: 22692830
Cell Rep. 2021 Dec 28;37(13):110175
pubmed: 34965427
Immunity. 2009 Jul 17;31(1):25-34
pubmed: 19576794
J Mol Biol. 2000 Jun 30;300(1):221-32
pubmed: 10864511
Proc Natl Acad Sci U S A. 2016 Jan 19;113(3):596-601
pubmed: 26733676
Nat Commun. 2017 Oct 13;8(1):923
pubmed: 29030554
Immunity. 2015 Jul 21;43(1):41-51
pubmed: 26187414
EMBO J. 2022 May 16;41(10):e109782
pubmed: 35437807
J Am Soc Mass Spectrom. 2013 Dec;24(12):1906-12
pubmed: 24018862
Adv Virus Res. 2000;55:135-84
pubmed: 11050942
Immunity. 2021 Oct 12;54(10):2218-2230.e5
pubmed: 34644557
Proc Natl Acad Sci U S A. 2013 Apr 16;110(16):6459-64
pubmed: 23553835
Cell. 2011 Oct 14;147(2):409-22
pubmed: 22000018
Immunity. 2012 Jun 29;36(6):959-73
pubmed: 22705106
Annu Rev Biophys. 2008;37:317-36
pubmed: 18573084
Biochemistry. 2011 Jul 5;50(26):5958-68
pubmed: 21657794
Nat Struct Mol Biol. 2015 Jun;22(6):492-8
pubmed: 25938660
Nano Lett. 2019 Sep 11;19(9):5982-5990
pubmed: 31389241
Nat Genet. 2014 May;46(5):503-509
pubmed: 24686847
Nature. 2014 May 1;509(7498):110-4
pubmed: 24590070
Nucleic Acids Res. 2015 Jan;43(2):1216-30
pubmed: 25539915
Nat Commun. 2016 Jul 07;7:11966
pubmed: 27384267
Cell. 2010 Apr 16;141(2):315-30
pubmed: 20403326
Curr Opin Struct Biol. 2019 Oct;58:305-313
pubmed: 31351767
Annu Rev Biochem. 2004;73:705-48
pubmed: 15189157
Nucleic Acids Res. 2016 Sep 19;44(16):7511-26
pubmed: 27317694
Ann Rheum Dis. 2008 Jan;67(1):137-8
pubmed: 18077546
Nature. 2014 Oct 16;514(7522):372-375
pubmed: 25119032
J Clin Immunol. 2019 Jan;39(1):75-80
pubmed: 30574673
Nature. 2011 Sep 25;479(7373):423-7
pubmed: 21947008
Nucleic Acids Res. 2016 Jan 29;44(2):896-909
pubmed: 26612866
Nat Immunol. 2004 Jul;5(7):730-7
pubmed: 15208624
Elife. 2016 Mar 02;5:
pubmed: 26933836
EMBO Rep. 2013 Sep;14(9):772-9
pubmed: 23897087
Science. 2009 Jan 30;323(5914):638-41
pubmed: 19179532
RNA Biol. 2013 Jan;10(1):111-20
pubmed: 23228901
Phys Rev Lett. 2020 Nov 6;125(19):198101
pubmed: 33216575
Nucleic Acids Res. 2021 Sep 27;49(17):9978-9991
pubmed: 34403472
PLoS Genet. 2013;9(2):e1003222
pubmed: 23441136
Am J Hum Genet. 2015 Feb 5;96(2):266-74
pubmed: 25620203
Mol Cell. 2015 Feb 5;57(3):397-407
pubmed: 25557550
Cell. 2011 Oct 14;147(2):423-35
pubmed: 22000019
Nat Commun. 2018 Dec 18;9(1):5366
pubmed: 30560918
Nature. 2007 Aug 16;448(7155):816-9
pubmed: 17653195
Adv Exp Med Biol. 2013;767:47-73
pubmed: 23161006
Science. 2009 Apr 17;324(5925):387-9
pubmed: 19264985
J Med Genet. 2022 Mar;59(3):294-304
pubmed: 33495304
Angew Chem Int Ed Engl. 2014 Sep 8;53(37):9751-4
pubmed: 25049220
Cell Res. 2021 Oct;31(10):1047-1060
pubmed: 34465913
Mol Cell. 2019 Mar 7;73(5):1015-1027.e7
pubmed: 30711376
Sci Adv. 2019 Dec 18;5(12):eaav2720
pubmed: 31897422
J Am Soc Mass Spectrom. 2006 Nov;17(11):1498-1509
pubmed: 16875839
Nat Rev Immunol. 2020 Sep;20(9):537-551
pubmed: 32203325