Leader-Containing Uncapped Viral Transcript Activates RIG-I in Antiviral Stress Granules

Oh, Seong Wook; Onomoto, Koji; Wakimoto, Mai; Onoguchi, Kazuhide; Ishidate, Fumiyoshi; Fujiwara, Takeshi; Yoneyama, Mitsutoshi; Kato, Hiroki; Fujita, Takashi

doi:10.1371/journal.ppat.1005444

Cited by 74 publications

(103 citation statements)

References 48 publications

(51 reference statements)

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“…Rather than being inert structures, recent reports suggest SGs have antiviral properties; the granules concentrate and promote interactions between a number of innate immune activators, their downstream interferon-stimulated genes (RIG-I, PKR, MDA5, and OAS), and their targets (5,41,43). For example, pattern recognition receptors like RIG-I are activated upon binding to viral RNAs in SGs, which leads to the stimulation of interferon-related genes (42,43,82). Alternatively, recent studies suggest that in the absence of virus infection, SGs can activate innate immune signaling (11,83,84).…”

Section: Discussionmentioning

confidence: 99%

Disruption of Stress Granule Formation by the Multifunctional Cricket Paralysis Virus 1A Protein

Khong

Kerr

Yeung

et al. 2017

J Virol

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Stress granules (SGs) are cytosolic ribonucleoprotein aggregates that are induced during cellular stress. Several viruses modulate SG formation, suggesting that SGs have an impact on virus infection. However, the mechanisms and impact of modulating SG assembly in infected cells are not completely understood. In this study, we identify the dicistrovirus cricket paralysis virus 1A (CrPV-1A) protein that functions to inhibit SG assembly during infection. Moreover, besides inhibiting RNA interference, CrPV-1A also inhibits host transcription, which indirectly modulates SG assembly. Thus, CrPV-1A is a multifunctional protein. We identify a key R146A residue that is responsible for these effects, and mutant CrPV(R146A) virus infection is attenuated in Drosophila melanogaster S2 cells and adult fruit flies and results in increased SG formation. Treatment of CrPV(R146A)-infected cells with actinomycin D, which represses transcription, restores SG assembly suppression and viral yield. In summary, CrPV-1A modulates several cellular processes to generate a cellular environment that promotes viral translation and replication.IMPORTANCE RNA viruses encode a limited set of viral proteins to modulate an array of cellular processes in order to facilitate viral replication and inhibit antiviral defenses. In this study, we identified a viral protein, called CrPV-1A, within the dicistrovirus cricket paralysis virus that can inhibit host transcription, modulate viral translation, and block a cellular process called stress granule assembly. We also identified a specific amino acid within CrPV-1A that is important for these cellular processes and that mutant viruses containing mutations of CrPV-1A attenuate virus infection. We also demonstrate that the CrPV-1A protein can also modulate cellular processes in human cells, suggesting that the mode of action of CrPV-1A is conserved. We propose that CrPV-1A is a multifunctional, versatile protein that creates a cellular environment in virus-infected cells that permits productive virus infection.

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Section: Discussionmentioning

confidence: 99%

Disruption of Stress Granule Formation by the Multifunctional Cricket Paralysis Virus 1A Protein

Khong

Kerr

Yeung

et al. 2017

J Virol

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“…GQ849007.1), and found that it contains 5′ppp and 3′poly(A + ). This RNA and the viral replication complex was shown to actually colocalize in cytoplasmic antiviral stress granules along with cellular RIG-I [53]. Similar IFN-inducing read-through RNA species were also confirmed in two other NNR viruses, namely vesicular stomatitis virus (Le-N) and RSV (Le-NS1).…”

Section: Evaluation Of Nnr Viral Rnas As a Potential Rig-i Ligandmentioning

confidence: 76%

“…The most recent hunt for RIG-I ligands have implicated the NNR viral LeRT transcript [53]. Specifically, a fraction of the LeRNA that reads through its transcription termination site into the next gene, generating what we will call ‘Leader-read-through' or LeRT RNA, was shown to be a major inducer of IFN via RIG-I [53].…”

Section: Evaluation Of Nnr Viral Rnas As a Potential Rig-i Ligandmentioning

confidence: 99%

“…Specifically, a fraction of the LeRNA that reads through its transcription termination site into the next gene, generating what we will call ‘Leader-read-through' or LeRT RNA, was shown to be a major inducer of IFN via RIG-I [53]. These authors used Newcastle disease virus, an NNR virus, in which the leader sequence is followed by the nucleocapsid protein gene, N. They identified the Newcastle disease virus LeRT RNA as the 1.8-kb-long Le-N RNA (GenBank No.…”

Section: Evaluation Of Nnr Viral Rnas As a Potential Rig-i Ligandmentioning

confidence: 99%

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What Really Rigs Up RIG-I?

Barik¹

2016

J Innate Immun

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RIG-I (retinoic acid-inducible gene 1) is an archetypal member of the cytoplasmic DEAD-box dsRNA helicase family (RIG-I-like receptors or RLRs), the members of which play essential roles in the innate immune response of the metazoan cell. RIG-I functions as a pattern recognition receptor that detects nonself RNA as a pathogen-associated molecular pattern (PAMP). However, the exact molecular nature of the viral RNAs that act as a RIG-I ligand has remained a mystery and a matter of debate. In this article, we offer a critical review of the actual viral RNAs that act as PAMPs to activate RIG-I, as seen from the perspective of a virologist, including a recent report that the viral Leader-read-through transcript is a novel and effective RIG-I ligand.

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“…However, it is important to bear in mind that SGs are being increasingly viewed as more than a mere consequence of a cell's stress response or a temporary storage depot for mRNPs. Two independent research groups have shown that SGs can promote innate immune responses (76)(77)(78)(79). This has led to the proposal that SGs serve as platforms for recognizing and responding to viral infections (80), which may explain why so many viruses destroy or modify SGs during infection and necessitates a better understanding of SG biology.…”

Section: Discussionmentioning

confidence: 99%

Herpes Simplex Virus 2 Virion Host Shutoff Endoribonuclease Activity Is Required To Disrupt Stress Granule Formation

Finnen

Zhu

et al. 2016

J Virol

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We previously established that cells infected with herpes simplex virus 2 (HSV-2) are disrupted in their ability to form stress granules (SGs) in response to oxidative stress and that this disruption is mediated by virion host shutoff protein (vhs), a virionassociated endoribonuclease. Here, we test the requirement for vhs endoribonuclease activity in disruption of SG formation. We analyzed the ability of HSV-2 vhs carrying the point mutation D215N, which ablates its endoribonuclease activity, to disrupt SG formation in both transfected and infected cells. We present evidence that ablation of vhs endoribonuclease activity results in defects in vhs-mediated disruption of SG formation. Furthermore, we demonstrate that preformed SGs can be disassembled by HSV-2 infection in a manner that requires vhs endoribonuclease activity and that, befitting this ability to promote SG disassembly, vhs is able to localize to SGs. Together these data indicate that endoribonuclease activity must be maintained in order for vhs to disrupt SG formation. We propose a model whereby vhs-mediated destruction of SG mRNA promotes SG disassembly and may also prevent SG assembly. IMPORTANCEStress granules (SGs) are transient cytoplasmic structures that form when a cell is exposed to stress. SGs are emerging as potential barriers to viral infection, necessitating a more thorough understanding of their basic biology. We identified virion host shutoff protein (vhs) as a herpes simplex virus 2 (HSV-2) protein capable of disrupting SG formation. As mRNA is a central component of SGs and the best-characterized activity of vhs is as an endoribonuclease specific for mRNA in vivo, we investigated the requirement for vhs endoribonuclease activity in disruption of SG formation. Our studies demonstrate that endoribonuclease activity is required for vhs to disrupt SG formation and, more specifically, that SG disassembly can be driven by vhs endoribonuclease activity. Notably, during the course of these studies we discovered that there is an ordered departure of SG components during their disassembly and, furthermore, that vhs itself has the capacity to localize to SGs. Stress granules (SGs) are dynamic, non-membrane-bound cytoplasmic compartments that contain translationally silent mRNAs that remain associated with a cadre of translation initiation proteins, poly(A) binding protein (PABP), and the small ribosomal subunit in the form of messenger ribonucleoprotein complexes (mRNPs) (1). SGs assemble rapidly in response to a variety of stressful conditions and likewise can disassemble rapidly when stress is alleviated. Natural stresses that eukaryotic cells encounter include starvation, elevated temperature (heat shock), oxidation, and virus infection, all of which can be sensed by four distinct eukaryotic initiation factor 2 (eIF2) kinases. Following the sensing of stress, these kinases become activated and phosphorylate the alpha subunit of eIF2 (eIF2␣), leading to a failure to initiate new rounds of translation (2). The ensuing stoppage in prote...

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Leader-Containing Uncapped Viral Transcript Activates RIG-I in Antiviral Stress Granules

Cited by 74 publications

References 48 publications

Disruption of Stress Granule Formation by the Multifunctional Cricket Paralysis Virus 1A Protein

Disruption of Stress Granule Formation by the Multifunctional Cricket Paralysis Virus 1A Protein

What Really Rigs Up RIG-I?

Herpes Simplex Virus 2 Virion Host Shutoff Endoribonuclease Activity Is Required To Disrupt Stress Granule Formation

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