The intrinsically disordered CARDs-Helicase linker in RIG-I is a molecular gate for RNA proofreading.
RIG-I
RNA discrimination
intrinsically disordered linker
regulatory region
self-vs-non-self
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
16 05 2022
16 05 2022
Historique:
revised:
28
03
2022
received:
22
09
2021
accepted:
04
04
2022
pubmed:
20
4
2022
medline:
18
5
2022
entrez:
19
4
2022
Statut:
ppublish
Résumé
The innate immune receptor RIG-I provides a first line of defense against viral infections. Viral RNAs are recognized by RIG-I's C-terminal domain (CTD), but the RNA must engage the helicase domain to release the signaling CARD (Caspase Activation and Recruitment Domain) domains from their autoinhibitory CARD2:Hel2i interactions. Because the helicase itself lacks RNA specificity, mechanisms to proofread RNAs entering the helicase domain must exist. Although such mechanisms would be crucial in preventing aberrant immune responses by non-specific RNAs, they remain largely uncharacterized to date. This study reveals a previously unknown proofreading mechanism through which RIG-I ensures that the helicase engages RNAs explicitly recognized by the CTD. A crucial part of this mechanism involves the intrinsically disordered CARDs-Helicase Linker (CHL), which connects the CARDs to the helicase subdomain Hel1. CHL uses its negatively charged regions to antagonize incoming RNAs electrostatically. In addition to this RNA gating function, CHL is essential for stabilization of the CARD2:Hel2i interface. Overall, we uncover that the CHL and CARD2:Hel2i interface work together to establish a tunable gating mechanism that allows CTD-chosen RNAs to bind the helicase domain, while at the same time blocking non-specific RNAs. These findings also indicate that CHL could represent a novel target for RIG-I-based therapeutics.
Identifiants
pubmed: 35437807
doi: 10.15252/embj.2021109782
pmc: PMC9108607
doi:
Substances chimiques
RNA, Double-Stranded
0
RNA, Viral
0
DNA Helicases
EC 3.6.4.-
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, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e109782Subventions
Organisme : NIAID NIH HHS
ID : R21 AI128264
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM118086
Pays : United States
Informations de copyright
© 2022 The Authors. Published under the terms of the CC BY 4.0 license.
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