RIG-I recognizes metabolite-capped RNAs as signaling ligands.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
25 08 2023
25 08 2023
Historique:
accepted:
12
06
2023
received:
06
10
2022
medline:
28
8
2023
pubmed:
16
6
2023
entrez:
16
6
2023
Statut:
ppublish
Résumé
The innate immune receptor RIG-I recognizes 5'-triphosphate double-stranded RNAs (5' PPP dsRNA) as pathogenic RNAs. Such RNA-ends are present in viral genomes and replication intermediates, and they activate the RIG-I signaling pathway to produce a potent interferon response essential for viral clearance. Endogenous mRNAs cap the 5' PPP-end with m7G and methylate the 2'-O-ribose to evade RIG-I, preventing aberrant immune responses deleterious to the cell. Recent studies have identified RNAs in cells capped with metabolites such as NAD+, FAD and dephosphoCoA. Whether RIG-I recognizes these metabolite-capped RNAs has not been investigated. Here, we describe a strategy to make metabolite-capped RNAs free from 5' PPP dsRNA contamination, using in vitro transcription initiated with metabolites. Mechanistic studies show that metabolite-capped RNAs have a high affinity for RIG-I, stimulating the ATPase activity at comparable levels to 5' PPP dsRNA. Cellular signaling assays show that the metabolite-capped RNAs potently stimulate the innate antiviral immune response. This demonstrates that RIG-I can tolerate diphosphate-linked, capped RNAs with bulky groups at the 5' RNA end. This novel class of RNAs that stimulate RIG-I signaling may have cellular roles in activating the interferon response and may be exploited with proper functionalities for RIG-I-related RNA therapeutics.
Identifiants
pubmed: 37326006
pii: 7199333
doi: 10.1093/nar/gkad518
pmc: PMC10450190
doi:
Substances chimiques
DEAD Box Protein 58
EC 3.6.4.13
DEAD-box RNA Helicases
EC 3.6.4.13
Interferons
9008-11-1
Ligands
0
RNA Caps
0
RNA, Double-Stranded
0
RNA, Viral
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
8102-8114Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM118086
Pays : United States
Informations de copyright
© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.
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