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

ABSTRACT: OAS1/RNase L executes 5’-triphosphate RNA-dependent tumor cell apoptosis

PROVIDER: PRJNA633110 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11797249.fastq.gz	Fastqsanger.gz
	SRR11797250.fastq.gz	Fastqsanger.gz
	SRR11797251.fastq.gz	Fastqsanger.gz
	SRR11797252.fastq.gz	Fastqsanger.gz
	SRR11797253.fastq.gz	Fastqsanger.gz

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Similar Datasets

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

Project description: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.

2021-05-12 | GSE150658 | GEO

Heterozygous OAS1 Gain-of-Function Variants Cause a Polymorphic Autoinflammatory and Immunodeficiency Syndrome

Project description:Oligoadenylate synthase 1 (OAS1) is a type-1 interferon-inducible, intracellular double-stranded RNA (dsRNA) sensor that generates 2'-5'-oligoadenylate (2-5A) to activate RNaseL as a means of antiviral defense. We report four de novo heterozygous OAS1 variants in five patients. Variant OAS1 proteins show dsRNA-independent gain-of-function 2-5A synthetase activity that results in RNaseL-mediated RNA-cleavage, transcriptomic downregulation, and functional impairment and/or apoptosis of monocytes, iPSC-derived macrophages, and B-cells. This leads to a polymorphic syndrome of monocyte, macrophage, and B-cell deficiency characterized by autoinflammation, pulmonary alveolar proteinosis, and hypogammaglobulinemia. RNase-L-inhibition in vitro mitigates, and hematopoietic cell transplantation in vivo corrects the autoinflammatory and immunodeficiency phenotype.

2021-06-18 | GSE173667 | GEO

Initiation of a ZAKa-dependent Ribotoxic Stress Response by the Innate Immunity Endoribonuclease RNase L

Project description:RNase L is a regulated endoribonuclease in higher vertebrates that functions in antiviral innate immunity. Interferons induce OAS enzymes that sense double-stranded RNA of viral origin leading to synthesis of 2’,5’-oligoadenylate (2-5A) activators of RNase L. However, it is unknown precisely how RNase L modulates host transcriptome through its endoribonuclease activity. To isolate effects of RNase L from other effects of double-stranded RNA or virus, 2-5A was directly introduced into cells. Here we report that RNase L activation by 2-5A causes a ribotoxic stress response that requires the ribosome-associated MAP3K, ZAK. Subsequently, the stress-activated protein kinases (SAPK) JNK and p38 are phosphorylated. RNase L activation profoundly altered the transcriptome by widespread depletion of mRNAs associated with different cellular functions, but also by SAPK-dependent induction of inflammatory genes. Our findings show that 2-5A is a ribotoxic stressor that causes RNA damage through RNase L triggering a ZAK kinase cascade leading to proinflammatory signaling and apoptosis.

2024-03-01 | GSE253530 | GEO

Switching of OAS1 splicing isoforms mitigates SARS-CoV-2 infection

Project description:We aimed to study impact of CDC-like kinase (CLK) inhibitor CaNDY on OAS1 splicing manipulation. Our data indicates CaNDY treatment induces switching of OAS1 splice isoforms to provide an increased resistance to SARS-CoV-2 infection.

2021-08-02 | GSE174398 | GEO

RNA-Sequencing of EndoC-BH1 cells Overexpressing OAS1, OAS2, or OAS3

Project description:EndoC-BH1 cells were plated in normal media and forward transfected with lipofectamine 3000 (2ug cDNA) of empty, OAS1, OAS2, or OAS3 plasmids from Vector builder

2024-01-01 | GSE244273 | GEO

RNase H dependent Antisense oligonucleotides in the nucleus causes transcription termination

Project description:RNase H dependent Antisense oligonucleotides in the nucleus causes transcription termination

| PRJNA551276 | ENA

OAS1 and OAS3 negatively regulate the expression of chemokines and interferon-responsive genes in human macrophages

Project description:We report analysis of mRNA profiles from wild-type and OAS1 and OAS3-KO human cell lines stimulated with PolyI:C.

2021-04-19 | GSE113363 | GEO

Genome-wide alterations in yeast strains lacking RNase H1, RNase H2, or both RNase H1 and RNase H2

Project description:Two types of RNA:DNA associations can lead to genome instability: the formation of R-loops during transcription and the incorporation of ribonucleotide monophosphates (rNMPs) into DNA during replication. Both ribonuclease (RNase) H1 and RNase H2 degrade the RNA component of R-loops, whereas only RNase H2 can remove one or a few rNMPs from DNA. We performed high-resolution mapping of mitotic recombination events throughout the yeast genome in diploid strains of Saccharomyces cerevisiae lacking RNase H1 (rnh1Δ), RNase H2 (rnh201Δ), or both RNase H1 and RNase H2 (rnh1Δ rnh201Δ). We found little effect on recombination in the rnh1Δ strain, but elevated recombination in both the rnh201Δ and the double-mutant strains; levels of recombination in the double mutant were about 50% higher than in the rnh201 single-mutant strain. An rnh201Δ mutant that additionally contained a mutation that reduces rNMP incorporation by DNA polymerase ε (pol2-M644L) had a level of instability similar to that observed in the presence of wild-type Polε. This result suggests that the elevated recombination observed in the absence of only RNase H2 is primarily a consequence of R loops rather than misincorporated rNMPs.

2015-09-23 | GSE73334 | GEO

Proteomic profiling of RNase III-dependent asRNA regulation in E. coli

Project description:In an effort to determine if the RNase III-dependent asRNA regulation had an effect on protein production in E. coli we conducted two TMT 6-plex experiments comparing cultures of wildtype E. coli, rnc-14, rnc-38, hfq in the stationary and exponential phase.

2020-06-18 | PXD011180 | Pride

ATP-Competitive Partial Antagonists—'PAIR's—Segregate IRE1α’s RNase-Mediated Biological Outputs

Project description:During mammalian cell growth and differentiation, the unfolded protein response (UPR) homeostatically adjusts endoplasmic reticulum (ER) protein-folding capacity to match changing cellular secretory demands. However, under high/chronic ER stress conditions the UPR triggers apoptosis. This dichotomy is promoted in part by differential activation levels of the ER transmembrane kinase/endoribonuclease (RNase) IRE1a. IRE1a kinase auto-phosphorylation operates as a rheostat to control downstream RNase-induced outputs that either sustain adaptive ER protein-folding or cause apoptosis. We have previously shown that IRE1a’s RNase activity can be activated or fully inactivated by ATP-competitive kinase inhibitors. Here we developed a new class of ATP-competitive kinase inhibitors that partially antagonize the RNase of IRE1a at full occupancy. An atomic level resolution co-crystal structure shows that these small molecule partial antagonists—which we named ‘PAIR’s for (Partial Antagonists of IRE1a RNase)—occupy the ATP-binding site of IRE1a and partially displace a helix (helix aC) in the kinase domain that forms part of a dimeric interface. In insulin-producing beta cells, PAIRs permit adaptive XBP1 mRNA splicing, while quelling destructive/terminal outputs from extra-XBP1 mRNA endonucleolytic decay, thus preventing apoptosis. Preservation of XBP1 splicing by PAIRs permits B lymphocytes to differentiate into immunoglobulin-producing plasma cells. In summary, we propose that an intermediate RNase-inhibitory “sweet spot,” achieved by PAIR-bound IRE1a, may capture a structural conformation naturally available to IRE1a that could represent a desirable therapeutic state for drugging this master UPR sensor/effector.

2021-06-01 | GSE164496 | GEO

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