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

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

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  • Medientyp: E-Artikel
  • Titel: A conserved isoleucine in the binding pocket of RIG-I controls immune tolerance to mitochondrial RNA
  • Beteiligte: de Regt, Ann Kristin; Anand, Kanchan; Ciupka, Katrin; Bender, Felix; Gatterdam, Karl; Putschli, Bastian; Fusshöller, David; Hilbig, Daniel; Kirchhoff, Alexander; Hunkler, Charlotte; Wolter, Steven; Grünewald, Agathe; Wallerath, Christina; Schuberth-Wagner, Christine; Ludwig, Janos; Paeschke, Katrin; Bartok, Eva; Hagelueken, Gregor; Hartmann, Gunther; Zillinger, Thomas; Geyer, Matthias; Schlee, Martin
  • Erschienen: Oxford University Press (OUP), 2023
  • Erschienen in: Nucleic Acids Research
  • Sprache: Englisch
  • DOI: 10.1093/nar/gkad835
  • ISSN: 0305-1048; 1362-4962
  • Schlagwörter: Genetics
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title> <jats:p>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.</jats:p>
  • Zugangsstatus: Freier Zugang