RNase L Targets Distinct Sites in Influenza A Virus RNAs

Cooper, Daphne A.; Banerjee, Shuvomoy; Chakrabarti, Arindam; Garcı́a-Sastre, Adolfo; Hesselberth, Jay R.; Silverman, Robert H.; Barton, David J.

doi:10.1128/jvi.02953-14

Cited by 50 publications

(53 citation statements)

References 53 publications

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“…Given the selection for OAS isoforms and the recent implication of the OAS/RNAseL system in MDA5 activation (Luthra et al, 2011; Malathi et al, 2007), we next investigated whether this intrinsic cellular defense against IAV was responsible for amplifying the host antiviral response. Indeed, this same pathway has been suggested to be an effective antiviral activity against IAV and one of the primary targets of the NS1 protein (Cooper et al, 2015; Min and Krug, 2006). Moreover, the recent finding that MDA5 aids in exposing viral dsRNA to the host machinery would suggest that MDA5 could enhance the activity of the OAS/RNAseL system (Yao et al, 2015).…”

Section: Resultsmentioning

confidence: 96%

In Vivo RNAi Screening Identifies MDA5 as a Significant Contributor to the Cellular Defense against Influenza A Virus

et al. 2015

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SUMMARY Responding to an influenza A virus (IAV) infection demands an effective intrinsic cellular defense strategy to slow replication. To identify contributing host factors to this defense, we exploited the host microRNA pathway to perform an in vivo RNAi screen. To this end, IAV, lacking a functional NS1 antagonist, was engineered to encode individual siRNAs against antiviral host genes in an effort to rescue attenuation. This screening platform resulted in the enrichment of strains targeting virus-activated transcription factors, specific antiviral effectors, and intracellular pattern recognition receptors (PRRs). Interestingly, in addition to RIG-I, the PRR for IAV, a virus with the capacity to silence MDA5 also emerged as a dominant strain in wild type, but not in MDA5-deficient mice. Transcriptional profiling of infected knockout cells confirmed RIG-I to be the primary PRR for IAV but implicated MDA5 as a significant contributor to the cellular defense against influenza A virus.

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Section: Resultsmentioning

confidence: 96%

In Vivo RNAi Screening Identifies MDA5 as a Significant Contributor to the Cellular Defense against Influenza A Virus

et al. 2015

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“…The influenza A virus (IAV) non-structural 1 protein (NS1) contains an N-terminal RNA-binding domain which binds to and sequesters dsRNA, the activator of OAS [39][40][41]. RNase L inhibits IAV (NS1-mutant) replication by cleaving viral genomic RNA in sites encoding PB2, PB1, and PA proteins critical for viral replication [42]. In a similar mechanism, the herpes simplex virus type 1 (HSV1) US11 gene product [43] and vaccinia virus (VacV) E3L protein binds dsRNA to inhibit the innate immune response [44][45][46].…”

Section: Cellular and Viral Inhibitors Of Oas-rnase Lmentioning

confidence: 99%

“…RNase L cleaves cellular and viral RNAs within single-stranded regions after a UN dinucleotide (with a preference in the order of UU > UA ) UG > UC). Studies focused on identifying the RNA targets of RNase L have provided some insight on cellular and viral targets [18,42,84,85]. A recent microarray-based study identified certain target mRNAs regulated by RNase L activation.…”

Section: Rnase L Cleavagementioning

confidence: 99%

“…None of these studies focused on RNase L cleavage sites on viral RNAs, however. In a recent modified RNA sequencing study by Cooper and colleagues [18,42], RNase L target sites in the cellular RNAs (rRNA, snRNA such as U6 and U3) and also specific mapping of the viral RNAs (HCV, IAV, polio virus) were precisely mapped. The method used exploits the 2 0 -3 0 cyclic phosphate at the 3 0 end of the cleaved RNA (which is a characteristic of metal ionindependent RNases) and employs 2 0 -3 0 cyclic phosphate cDNA synthesis with Illumina sequencing to map RNase L targets from either in vitro cleaved RNAs or RNAs from virus-infected cells.…”

Section: Rnase L Cleavagementioning

confidence: 99%

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New advances in our understanding of the “unique” RNase L in host pathogen interaction and immune signaling

2020

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Ever since the discovery of the existence of an interferon (IFN)-regulated ribonuclease, significant advances have been made in understanding the mechanism and associated regulatory effects of its action. What had been studied initially as a "unique" endoribonuclease is currently known as ribonuclease L (RNase L where "L" stands for latent). Some of the key developments include discovery of the RNase L signaling pathway, its structural characterization, and its molecular cloning. RNase L has been implicated in antiviral and antibacterial defense, as well as in hereditary prostate cancer. RNase L is activated by 2'-5' linked oligoadenylates (2-5A), which are synthesized by the oligoadenylate synthetases (OASs), a family of IFN-regulated pathogen recognition receptors that sense double-stranded RNAs. Activated RNase L cleaves single stranded RNAs, including viral RNAs and cellular RNAs. The catalytic activity of RNase L has been found to lead into the activation of several cellular signaling pathways, including those involved in autophagy, apoptosis, IFN-β production, NLRP3 inflammasome activation leading to IL-1β secretion, inhibition of cell migration, and cell adhesion. In this review, we will highlight the newest advances in our understanding of the catalytic role of RNase L in the context of different cellular pathways and extend the scope of these findings to discussion of potential therapeutic targets for antimicrobial drug development.

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“…Furthermore, it has been found that RNA sequence is very specific for ribonucleases (for example, RNase H) [60–62]. To understand the substrate sequence specificity and site specificity, deep sequencing methods (for review see [63–65]) were used to investigate the frequency and locations of ribonuclease L cleavage sites of viral RNAs [66, 67]. Site-specific studies have also been carried out, using primer extension reactions to characterize ribonuclease L specific cleavage sites in hepatitis C virus RNA [68] and DNA damage sites [69].…”

Section: Techniques For Multiplexed High Throughput Measurements mentioning

confidence: 99%

Measuring specificity in multi-substrate/product systems as a tool to investigate selectivity in vivo

Kuo

Henry

Andrews

2016

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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Multiple substrate enzymes present a particular challenge when it comes to understanding their activity in a complex system. Although a single target may be easy to model, it does not always present an accurate representation of what that enzyme will do in the presence of multiple substrates simultaneously. Therefore, there is a need to find better ways to both study these enzymes in complicated systems, as well as accurately describe the interactions through kinetic parameters. This review looks at different methods for studying multiple substrate enzymes, as well as explores options on how to most accurately describe an enzyme’s activity within these multi-substrate systems. Identifying and defining this enzymatic activity should clear the way ro use in vitro systems to accurately predict the behavior of multi-substrate enzymes in vivo.

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RNase L Targets Distinct Sites in Influenza A Virus RNAs

Abstract: Influenza

Cited by 50 publications

References 53 publications

In Vivo RNAi Screening Identifies MDA5 as a Significant Contributor to the Cellular Defense against Influenza A Virus

In Vivo RNAi Screening Identifies MDA5 as a Significant Contributor to the Cellular Defense against Influenza A Virus

New advances in our understanding of the “unique” RNase L in host pathogen interaction and immune signaling

Measuring specificity in multi-substrate/product systems as a tool to investigate selectivity in vivo

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