OAS1/RNase L executes RIG-I ligand-dependent tumor cell apoptosis

Boehmer, Daniel F. R.; Formisano, Simone; Mann, Carina C. de Oliveira; Mueller, Stephan A.; Kluge, Michael; Metzger, Philipp; Rohlfs, Meino; Hoerth, Christine; Kocheise, Lorenz; Lichtenthaler, Stefan F.; Hopfner, Karl-Peter; Endres, Stefan; Rothenfusser, Simon; Friedel, Caroline C.; Duewell, Peter; Schnurr, Max und Koenig, Lars M. (2021): OAS1/RNase L executes RIG-I ligand-dependent tumor cell apoptosis. In: Science Immunology, Bd. 6, Nr. 61, eabe2550

Abstract

Cytoplasmic double-stranded RNA is sensed by RIG-I-like receptors (RLRs), leading to induction of type I interferons (IFN-Is), proinflammatory cytokines, and apoptosis. Here, we elucidate signaling mechanisms that lead to cytokine secretion and cell death induction upon stimulation with the bona fide RIG-I ligand 5'-triphosphate RNA (3p-RNA) in tumor cells. We show that both outcomes are mediated by dsRNA-receptor families with RLR being essential for cytokine production and IFN-I-mediated priming of effector pathways but not for apoptosis. Affinity purification followed by mass spectrometry and subsequent functional analysis revealed that 3p-RNA bound and activated oligoadenylate synthetase 1 and RNase L. RNase L-deficient cells were profoundly impaired in their ability to undergo apoptosis. Mechanistically, the concerted action of translational arrest triggered by RNase L and up-regulation of NOXA was needed to deplete the antiapoptotic MCL-1 to cause intrinsic apoptosis. Thus, 3p-RNA-induced apoptosis is a two-step process consisting of RIG-I-dependent priming and an RNase L-dependent effector phase.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin ; Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2470-9468
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198