Journal Article

DZNE-2021-01397

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png OAS1/RNase L executes RIG-I ligand-dependent tumor cell apoptosis.

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

2021
AAAS Washington, DC

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Please use a persistent id in citations: 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.

Keyword(s): 2',5'-Oligoadenylate Synthetase: genetics (MeSH) ; 2',5'-Oligoadenylate Synthetase: immunology (MeSH) ; Adaptor Proteins, Signal Transducing: genetics (MeSH) ; Animals (MeSH) ; Apoptosis (MeSH) ; Cell Line, Tumor (MeSH) ; Coculture Techniques (MeSH) ; DEAD Box Protein 58: genetics (MeSH) ; Endoribonucleases: genetics (MeSH) ; Endoribonucleases: immunology (MeSH) ; Humans (MeSH) ; Interferon-Induced Helicase, IFIH1: genetics (MeSH) ; Ligands (MeSH) ; Mice (MeSH) ; Neoplasms: immunology (MeSH) ; Receptors, Immunologic: genetics (MeSH) ; Receptors, Retinoic Acid: immunology (MeSH)

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Contributing Institute(s):

1. Neuroproteomics (AG Lichtenthaler)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2021

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Essential Science Indicators ; IF >= 30 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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