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Boehmer, D.F.R.* ; Formisano, S.* ; de Oliveira Mann, C.C.* ; Mueller, S.A.* ; Kluge, M.* ; Metzger, P.* ; Rohlfs, M.* ; Hörth, C.* ; Kocheise, L.* ; Lichtenthaler, S.F.* ; Hopfner, K.P.* ; Endres, S. ; Rothenfußer, S. ; Friedel, C.C.* ; Duewell, P.* ; Schnurr, M.* ; Koenig, L.M.*

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

Sci. Immunol. 6:eabe2550 (2021)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Cancer-cells; 2-5a-dependent Rnase; Targeted Activation; 5'-triphosphate Rna; Protein-synthesis; Mcl-1; Death; Induction; Pathway; Triphosphate
ISSN (print) / ISBN 2470-9468
e-ISSN 2470-9468
Journal Science immunology
Quellenangaben Volume: 6, Issue: 61, Pages: , Article Number: eabe2550 Supplement: ,
Publisher American Association for the Advancement of Science (AAAS)
Publishing Place Washington, DC
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Unit for Clinical Pharmacology (KKG-EKLiP)
Grants Friedrich-Baur-Stiftung
Else KronerFresenius-Stiftung
international doctoral program "iTarget: Immunotargeting of cancer" - Elite Network of Bavaria
Marie-Sklodowska-Curie Training Network for the Immunotherapy of Cancer (IMMUTRAIN) - H2020 program of the European Union
Munich Cluster for Systems Neurology
Deutsche Forschungsgemeinschaft (DFG, German Research foundation)