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A conserved isoleucine in the binding pocket of RIG-I controls immune tolerance to mitochondrial RNA.

Nucleic acids research

Authors: Ann Kristin de Regt, Kanchan Anand, Katrin Ciupka, Felix Bender, Karl Gatterdam, Bastian Putschli, David Fusshöller, Daniel Hilbig, Alexander Kirchhoff, Charlotte Hunkler, Steven Wolter, Agathe Grünewald, Christina Wallerath, Christine Schuberth-Wagner, Janos Ludwig, Katrin Paeschke, Eva Bartok, Gregor Hagelueken, Gunther Hartmann, Thomas Zillinger, Matthias Geyer, Martin Schlee

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.

© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.

PMID: 37831086

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