OAS1/RNase L executes RIG-I ligand-dependent tumor cell apoptosis.
Sci Immunol
; 6(61)2021 07 16.
Article
in En
| MEDLINE
| ID: mdl-34272227
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
2',5'-Oligoadenylate Synthetase
/
Receptors, Retinoic Acid
/
Endoribonucleases
/
Neoplasms
Limits:
Animals
/
Humans
Language:
En
Journal:
Sci Immunol
Year:
2021
Document type:
Article
Affiliation country: