RNase L Attenuates Mitogen-stimulated Gene Expression via Transcriptional and Post-transcriptional Mechanisms to Limit the Proliferative Response

Brennan-Laun, Sarah E.; Li, Xiaoling; Ezelle, Heather J.; Venkataraman, Thiagarajan; Blackshear, Perry J.; Wilson, Gerald M.; Hassel, Bret A.

doi:10.1074/jbc.m114.589556

Cited by 21 publications

(16 citation statements)

References 112 publications

(152 reference statements)

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“…28,39 Emerging evidence that other RNases regulate gene expression post-transcriptionally through targeted mRNA degradation suggests the possibility that RNASET2 substrates could include mRNAs involved in antioxidant responses. [40][41][42] Identification of the relevant RNASET2 substrates in future studies will provide important insights into its impact on cellular oxidative stress responses.…”

Section: Discussionmentioning

confidence: 99%

RNASET2 is required for ROS propagation during oxidative stress-mediated cell death

et al. 2015

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RNASET2 is a ubiquitously expressed acidic ribonuclease that has been implicated in diverse pathophysiological processes including tumorigeneis, vitiligo, asthenozoospermia, and neurodegeneration. Prior studies indicate that RNASET2 is induced in response to oxidative stress and that overexpression of RNASET2 sensitizes cells to reactive oxygen species (ROS)-induced cell death through a mechanism that is independent of catalytic activity. Herein, we report a loss-of-function genetic screen that identified RNASET2 as an essential gene for lipotoxic cell death. Haploinsufficiency of RNASET2 confers increased antioxidant capacity and generalized resistance to oxidative stress-mediated cell death in cultured cells. This function is critically dependent on catalytic activity. Furthermore, knockdown of RNASET2 in the Drosophila fat body confers increased survival in the setting of oxidative stress inducers. Together, these findings demonstrate that RNASET2 regulates antioxidant tone and is required for physiological ROS responses.

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Section: Discussionmentioning

confidence: 99%

RNASET2 is required for ROS propagation during oxidative stress-mediated cell death

et al. 2015

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“…Accumulating evidence suggests that the OAS-RNase L system has virus-independent activities. RNase L was found to regulate the steady-state mRNA levels of certain genes involved in cell growth, proliferation, and differentiation (114)(115)(116). Whether this basal activity of RNase L requires 2-5A n and upstream OAS enzymes is unclear.…”

Section: Oligoadenylate Synthases and Rnase Lmentioning

confidence: 99%

Double-Stranded RNA Sensors and Modulators in Innate Immunity

Hur

2019

Annu. Rev. Immunol.

289

286

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Detection of double-stranded RNAs (dsRNAs) is a central mechanism of innate immune defense in many organisms. We here discuss several families of dsRNA-binding proteins involved in mammalian antiviral innate immunity. These include RIG-I-like receptors, protein kinase R, oligoadenylate synthases, adenosine deaminases acting on RNA, RNA interference systems, and other proteins containing dsRNA-binding domains and helicase domains. Studies suggest that their functions are highly interdependent and that their interdependence could offer keys to understanding the complex regulatory mechanisms for cellular dsRNA homeostasis and antiviral immunity. This review aims to highlight their interconnectivity, as well as their commonalities and differences in their dsRNA recognition mechanisms. KeywordsdsRNA; RIG-I-like receptor; protein kinase R; oligoadenylate synthase; dsRNA-dependent adenosine deaminase; RNA interference HHS Public Access

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“…RNase L | microRNA | miR-200 | adhesion | dsRNA R Nase L is a mammalian endoribonuclease regulated by the action of dsRNA and IFNs α/β/λ, which induce the intracellular synthesis of a specific RNase L activator, 2-5A (1). RNA cleavage is thought to account for all biological functions of the RNase L·2-5A complex, including innate immunity during the IFN response (2,3), and regulation of cell cycle (4), proliferation (5), adipocyte differentiation (6), and apoptosis (7). RNase L inhibits translation by site-specific cleavage of 18S and 28S rRNA (8) and activates transcription and the inflammasome NLRP3 by releasing signaling RNA fragments (2,9,10).…”

mentioning

confidence: 99%

Human RNase L tunes gene expression by selectively destabilizing the microRNA-regulated transcriptome

Rath

Donovan

Whitney

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Double-stranded RNA (dsRNA) activates the innate immune system of mammalian cells and triggers intracellular RNA decay by the pseudokinase and endoribonuclease RNase L. RNase L protects from pathogens and regulates cell growth and differentiation by destabilizing largely unknown mammalian RNA targets. We developed an approach for transcriptome-wide profiling of RNase L activity in human cells and identified hundreds of direct RNA targets and nontargets. We show that this RNase L-dependent decay selectively affects transcripts regulated by microRNA (miR)-17/miR-29/miR-200 and other miRs that function as suppressors of mammalian cell adhesion and proliferation. RNase L mimics the effects of these miRs and acts as a suppressor of proliferation and adhesion in mammalian cells. Our data suggest that RNase L-dependent decay serves to establish an antiproliferative state via destabilization of the miRregulated transcriptome.R Nase L is a mammalian endoribonuclease regulated by the action of dsRNA and IFNs α/β/λ, which induce the intracellular synthesis of a specific RNase L activator, 2-5A (1). RNA cleavage is thought to account for all biological functions of the RNase L·2-5A complex, including innate immunity during the IFN response (2, 3), and regulation of cell cycle (4), proliferation (5), adipocyte differentiation (6), and apoptosis (7). RNase L inhibits translation by site-specific cleavage of 18S and 28S rRNA (8) and activates transcription and the inflammasome NLRP3 by releasing signaling RNA fragments (2, 9, 10). These mechanisms complement or operate in parallel with posttranscriptional gene control via regulated decay of some mRNAs, including myogenic regulatory factor MyoD (11), components of IFN signaling ISG43 and ISG15 (12), translation-inhibiting kinase PKR (13), cathepsin E gastric protease (3), 3′-UTRbinding protein HuR (4), as well as ribosomal and mitochondrial protein-encoding mRNAs (14-16). Although the repression of these transcripts depends on RNase L, it remains unknown how many of them are cleaved physically and how many are downregulated indirectly-for example, via transcription.A recent RNA-sequencing (RNA-seq) study described some of the direct targets of RNase L (8). Cleavages were reported for 18S rRNA and U6 snRNA, however the experiment was designed to detect predominantly ribosomal reads and the direct impact of RNase L on mRNAs was not defined. Structural and biochemical studies found that RNase L cleaves RNA at the consensus sequence UN^N (N = A, U, G, or C;^is the cleavage location) (17-19). The UN^N motifs are abundant in all mammalian RNAs, suggesting that RNase L may degrade every mRNA it encounters, which surprisingly contrasts regulation of RNase L by the highly specific stimuli dsRNA, IFNs, and 2-5A.Mammalian cells contain a transmembrane RNase L homolog, a kinase/RNase Ire1, which drives the unfolded protein response and regulated Ire1-dependent decay (RIDD) (18,20). The cleavage consensus sequence of Ire1 (UĜC) is similarly relaxed, however Ire1 targets only specific mRNAs....

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RNase L Attenuates Mitogen-stimulated Gene Expression via Transcriptional and Post-transcriptional Mechanisms to Limit the Proliferative Response

Cited by 21 publications

References 112 publications

RNASET2 is required for ROS propagation during oxidative stress-mediated cell death

RNASET2 is required for ROS propagation during oxidative stress-mediated cell death

Double-Stranded RNA Sensors and Modulators in Innate Immunity

Human RNase L tunes gene expression by selectively destabilizing the microRNA-regulated transcriptome

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