Boehmer, D. F. R., Formisano, S., de Oliveira Mann, C. C., Mueller, S. A., Kluge, M., Metzger, P., Rohlfs, M., Horth, C., Kocheise, L., Lichtenthaler, S. F., Hopfner, K. P., Endres, S., Rothenfusser, S., Friedel, C. C., Duewell, P., Schnurr, M., and Koenig, L. M. (2021). Sci Immunol 6. doi: 10.1126/sciimmunol.abe2550

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.