OAS1/RNase L executes 5'-triphosphate RNA-dependent tumor cell apoptosis

Cytoplasmic double-stranded RNA is sensed by RIG-I-like receptors (RLR) leading to induction of type-I interferons (IFN-I), proinflammatory cytokines and apoptosis in tumor cells. Here, we elucidate the differential signaling mechanisms leading to cytokine secretion and/or cell death induction upon stimulation with the bona fide RIG-I ligand 5'-triphosphate RNA (3p-RNA). We show that both outcomes are mediated by distinct dsRNA-receptor families with RLR being essential for cytokine production and IFN-mediating priming of effector pathways, but not apoptosis itself. Affinity purification followed by mass spectrometry revealed 3p-RNA-specific binding and activation of oligoadenylate synthetase 1/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 upregulation of NOXA was needed to deplete anti-apoptotic MCL-1 causing intrinsic apoptosis. Thus, 3p-RNA-induced apoptosis is a two-step process consisting of a RIG-I-dependent priming and a RNase L-dependent effector phase. Overall design: mRNA sequencing of 1205Lu WT and RIG-I KO cells stimulated with 3p-RNA in presence or absence of IFN-?2a.