Concerted 2-5A-Mediated mRNA Decay and Transcription Reprogram Protein Synthesis in the dsRNA Response

Rath, Sneha; Prangley, Eliza; Donovan, Jesse; Demarest, Kaitlin; Wingreen, Ned S.; Meir, Yigal; Korennykh, Alexei

doi:10.1016/j.molcel.2019.07.027

Cited by 63 publications

(69 citation statements)

References 62 publications

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“…Furthermore, we have proposed that RNase L selectively degrades exogenous RNAs with Pelota-ABCE1 in a manner dependent on translation. Most recently, two reports have shown that under conditions that cells are treated with a potent trigger poly(I:C), RNase L degrades endogenous mRNAs, which is called 2-5A-mediated decay (2-5AMD) [31,32]. Interestingly, Rath et al demonstrated that RNase L activated by dsRNA degrades endogenous mRNAs, while RNase-L-resistant poly(A) + transcripts are enriched with noncoding RNAs, suggesting that RNase L sensitivity of RNA correlates with their translational activity [31].…”

Section: Discussionmentioning

confidence: 99%

“…Most recently, two reports have shown that under conditions that cells are treated with a potent trigger poly(I:C), RNase L degrades endogenous mRNAs, which is called 2-5A-mediated decay (2-5AMD) [31,32]. Interestingly, Rath et al demonstrated that RNase L activated by dsRNA degrades endogenous mRNAs, while RNase-L-resistant poly(A) + transcripts are enriched with noncoding RNAs, suggesting that RNase L sensitivity of RNA correlates with their translational activity [31]. The 2-5AMD is similar to the exogenous RNA decay in the sense that it seems to be dependent on 2-5A, RNase L and translation; however, in our condition that measures exogenous RNA decay, we detect specifically the degradation of exogenous RNA but can neither detect degradation of endogenous mRNAs nor rRNAs (e.g., Figure 2A, see GAPDH mRNA and rRNA).…”

Section: Discussionmentioning

confidence: 99%

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ABCE1 Acts as a Positive Regulator of Exogenous RNA Decay

Ogami

Oishi

Goda

et al. 2020

Viruses

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The 2′-5′-oligoadenylate synthetase (OAS)/RNase L system protects hosts against pathogenic viruses through cleavage of the exogenous single-stranded RNA. In this system, an evolutionally conserved RNA quality control factor Dom34 (known as Pelota (Pelo) in higher eukaryotes) forms a surveillance complex with RNase L to recognize and eliminate the exogenous RNA in a manner dependent on translation. Here, we newly identified that ATP-binding cassette sub-family E member 1 (ABCE1), which is also known as RNase L inhibitor (RLI), is involved in the regulation of exogenous RNA decay. ABCE1 directly binds to form a complex with RNase L and accelerates RNase L dimer formation in the absence of 2′-5′ oligoadenylates (2-5A). Depletion of ABCE1 represses 2-5A-induced RNase L activation and stabilizes exogenous RNA to a level comparable to that seen in RNase L depletion. The increased half-life of the RNA by the single depletion of either protein is not significantly affected by the double depletion of both proteins, suggesting that RNase L and ABCE1 act together to eliminate exogenous RNA. Our results indicate that ABCE1 functions as a positive regulator of exogenous RNA decay rather than an inhibitor of RNase L.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

ABCE1 Acts as a Positive Regulator of Exogenous RNA Decay

Ogami

Oishi

Goda

et al. 2020

Viruses

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“…Recently, two different laboratories made another important contribution to the understanding of how antiviral factors are preferentially produced in response to viral infections. They discovered that ribonuclease L (RNase L), which is activated in response to dsRNA, strongly depletes cellular mRNA pools through wide-spread mRNA degradation, but specifically leaves mRNAs encoding IFNs, cytokines, and other defense proteins intact [224][225][226]. The mechanism by which these mRNAs are excluded from RNase L-mediated cleavage remains unclear, but probably involves regulatory sequences, RNA secondary structures, and RBPs that protect individual mRNAs from degradation.…”

Section: Impact Of Stress Kinases On Innate Immune Signaling Pathwaysmentioning

confidence: 99%

Dance with the Devil: Stress Granules and Signaling in Antiviral Responses

Eiermann

Haneke

Sun

et al. 2020

Viruses

100

117

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Cells have evolved highly specialized sentinels that detect viral infection and elicit an antiviral response. Among these, the stress-sensing protein kinase R, which is activated by double-stranded RNA, mediates suppression of the host translation machinery as a strategy to limit viral replication. Non-translating mRNAs rapidly condensate by phase separation into cytosolic stress granules, together with numerous RNA-binding proteins and components of signal transduction pathways. Growing evidence suggests that the integrated stress response, and stress granules in particular, contribute to antiviral defense. This review summarizes the current understanding of how stress and innate immune signaling act in concert to mount an effective response against virus infection, with a particular focus on the potential role of stress granules in the coordination of antiviral signaling cascades.

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“…Furthermore, response to polyI:C varies in cell-type dependent manner, levels of OAS isoforms as well as abundance of polyI:C-binding proteins in cells (62). Recent reports show the role of RNase L in widespread mRNA degradation and translation repression of select basal mRNAs while antiviral mRNAs escaped decay and robustly translated (63, 64). These results suggest that RNA signaling and decay pathways activated by RNase L are complex and the dyamics may vary based on specific activation of RNase L by 2-5A compared to indirect activation by polyI:C as well as cell type differences and abundance of dsRNA-binding proteins including OAS isoforms.…”

Section: Discussionmentioning

confidence: 99%

RNase L amplifies Interferon signaling by inducing PKR-mediated antiviral stress granules

Manivannan

Siddiqui

Malathi

2020

Preprint

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ABSTRACTVirus infection leads to activation of the interferon-induced endoribonuclease, RNase L, which results in degradation of viral and cellular RNAs. Both cellular and viral RNA cleavage products of RNase L bind pattern recognition receptors (PRR) like Retinoic acid-inducible I (Rig-I) and or melanoma differentiation-associated protein 5 (MDA5) to further amplify interferon (IFN) production and antiviral response. Although much is known about the mechanics of ligand binding and PRR activation, how the cells coordinate RNA sensing to signaling response and interferon production remains unclear. We show that RNA cleavage products of RNase L activity induce formation of antiviral stress granule (avSG) by regulating activation of double-stranded RNA (dsRNA)-dependent protein kinase R (PKR), and recruit antiviral proteins Rig-I, PKR, OAS and RNase L to avSG. Biochemical analysis of purified avSG showed interaction of key stress granule protein, G3BP1, with only PKR and Rig-I and not with OAS or RNase L. AvSG assembly during RNase L activation is required for IRF3-mediated IFN production and not IFN signaling or proinflammatory cytokine induction. Consequently, cells lacking avSG formation or RNase L signaling produced less IFN and showed higher susceptibility during Sendai virus infection demonstrating the importance of avSG in RNase L-mediated host defense. During viral infection, we propose a role for RNase L-cleaved RNAs in inducing avSG containing antiviral proteins to provide a platform for efficient interaction of RNA ligands with pattern recognition receptors to enhance IFN production to effectively mount antiviral response.IMPORTANCEDouble-stranded RNAs produced during viral infections serve as pathogen associated molecular patterns (PAMPs) and bind pattern recognition receptors to stimulate IFN production. RNase L is an IFN-regulated endoribonuclease that is activated in virus-infected cells and cleaves single-stranded viral and cellular RNAs. The RNase L-cleaved dsRNAs signal to Rig-like helicases to amplify IFN production. This study identifies a novel role of antiviral stress granules induced by RNase L as an antiviral signaling hub to coordinate the RNA ligands with cognate receptors to mount effective host response during viral infections.

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Concerted 2-5A-Mediated mRNA Decay and Transcription Reprogram Protein Synthesis in the dsRNA Response

Cited by 63 publications

References 62 publications

ABCE1 Acts as a Positive Regulator of Exogenous RNA Decay

ABCE1 Acts as a Positive Regulator of Exogenous RNA Decay

Dance with the Devil: Stress Granules and Signaling in Antiviral Responses

RNase L amplifies Interferon signaling by inducing PKR-mediated antiviral stress granules

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