In:
Nucleic Acids Research, Oxford University Press (OUP), Vol. 51, No. 21 ( 2023-11-27), p. 11893-11910
Abstract:
RIG-I is a cytosolic receptor of viral RNA essential for the immune response to numerous RNA viruses. Accordingly, RIG-I must sensitively detect viral RNA yet tolerate abundant self-RNA species. The basic binding cleft and an aromatic amino acid of the RIG-I C-terminal domain(CTD) mediate high-affinity recognition of 5′triphosphorylated and 5′base-paired RNA(dsRNA). Here, we found that, while 5′unmodified hydroxyl(OH)-dsRNA demonstrated residual activation potential, 5′-monophosphate(5′p)-termini, present on most cellular RNAs, prevented RIG-I activation. Determination of CTD/dsRNA co-crystal structures and mutant activation studies revealed that the evolutionarily conserved I875 within the CTD sterically inhibits 5′p-dsRNA binding. RIG-I(I875A) was activated by both synthetic 5′p-dsRNA and endogenous long dsRNA within the polyA-rich fraction of total cellular RNA. RIG-I(I875A) specifically interacted with long, polyA-bearing, mitochondrial(mt) RNA, and depletion of mtRNA from total RNA abolished its activation. Altogether, our study demonstrates that avoidance of 5′p-RNA recognition is crucial to prevent mtRNA-triggered RIG-I-mediated autoinflammation.
Type of Medium:
Online Resource
ISSN:
0305-1048
,
1362-4962
Language:
English
Publisher:
Oxford University Press (OUP)
Publication Date:
2023
detail.hit.zdb_id:
1472175-2
SSG:
12
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