scholarly journals Puumala and Andes Orthohantaviruses Cause Transient Protein Kinase R-Dependent Formation of Stress Granules

2019 ◽  
Vol 94 (3) ◽  
Author(s):  
Wanda Christ ◽  
Janne Tynell ◽  
Jonas Klingström
Keyword(s):  
Protein Kinase ◽  
Host Cell ◽  
Stress Responses ◽  
Stress Granules ◽  
Cell Stress ◽  
Stress Granule ◽  
Hantavirus Infection ◽  
Stress Signaling ◽  
Protein Kinase R ◽  
Granule Formation

ABSTRACT Virus infection frequently triggers host cell stress signaling resulting in translational arrest; as a consequence, many viruses employ means to modulate the host stress response. Hantaviruses are negative-sense, single-stranded RNA viruses known to inhibit host innate immune responses and apoptosis, but their impact on host cell stress signaling remains largely unknown. In this study, we investigated activation of host cell stress responses during hantavirus infection. We show that hantavirus infection causes transient formation of stress granules (SGs) but does so in only a limited proportion of infected cells. Our data indicate some cell type-specific and hantavirus species-specific variability in SG prevalence and show SG formation to be dependent on the activation of protein kinase R (PKR). Hantavirus infection inhibited PKR-dependent SG formation, which could account for the transient nature and low prevalence of SG formation observed during hantavirus infection. In addition, we report only limited colocalization of hantaviral proteins or RNA with SGs and show evidence indicating hantavirus-mediated inhibition of PKR-like endoplasmic reticulum (ER) kinase (PERK). IMPORTANCE Our work presents the first report on stress granule formation during hantavirus infection. We show that hantavirus infection actively inhibits stress granule formation, thereby escaping the detrimental effects on global translation imposed by host stress signaling. Our results highlight a previously uncharacterized aspect of hantavirus-host interactions with possible implications for how hantaviruses are able to cause persistent infection in natural hosts and for pathogenesis.

scholarly journals The Stress Granule Protein G3BP1 Recruits Protein Kinase R To Promote Multiple Innate Immune Antiviral Responses

2014 ◽  
Vol 89 (5) ◽  
pp. 2575-2589 ◽  
Author(s):  
Lucas C. Reineke ◽  
Richard E. Lloyd
Keyword(s):  
Protein Kinase ◽  
Antiviral Activity ◽  
Cellular Stress ◽  
Stress Granules ◽  
Innate Immune ◽  
Stress Granule ◽  
Productive Infection ◽  
Antiviral Protein ◽  
Protein Kinase R ◽  
Transcriptional Responses

ABSTRACTStress granules (SGs) are cytoplasmic storage sites containing translationally silenced mRNPs that can be released to resume translation after stress subsides. We previously showed that poliovirus 3C proteinase cleaves the SG-nucleating protein G3BP1, blocking the ability of cells to form SGs late in infection. Many other viruses also target G3BP1 and inhibit SG formation, but the reasons why these functions evolved are unclear. Previously, we also showed a link between G3BP1-induced SGs and protein kinase R (PKR)-mediated translational control, but the mechanism of PKR interplay with SG and the antiviral consequences are unknown. Here, we show that G3BP1 exhibits antiviral activity against several enteroviruses, whereas truncated G3BP1 that cannot form SGs does not. G3BP1-induced SGs are linked to activation of innate immune transcriptional responses through NF-κB and JNK. The G3BP1-induced SGs also recruit PKR and other antiviral proteins. We show that the PXXP domain within G3BP1 is essential for the recruitment of PKR to SGs, for eIF2α phosphorylation driven by PKR, and for nucleating SGs of normal composition. We also show that deletion of the PXXP domain in G3BP1 compromises its antiviral activity. These findings tie PKR activation to its recruitment to SGs by G3BP1 and indicate that G3BP1 promotes innate immune responses at both the transcriptional and translational levels and integrates cellular stress responses and innate immunity.IMPORTANCEStress granules appear during virus infection, and their importance is not well understood. Previously, it was assumed that they were nonfunctional artifacts associated with cellular stress. PKR is a well-known antiviral protein; however, its regulation in cells is not well understood. Our work links cellular stress granules with activation of PKR and other innate immune pathways through the activity of G3BP1, a critical stress granule component. The ability of stress granules and G3BP1 to activate PKR and other innate immune transcriptional responses indicates that G3BP1 is an antiviral protein. This work helps to refine a longstanding paradigm indicating stress granules are inert structures and explains why G3BP1 is subverted by many viruses to promote a productive infection.

scholarly journals Infectious bronchitis virus regulates cellular stress granule signaling

2019 ◽  
Author(s):  
Matthew J. Brownsword ◽  
Nicole Doyle ◽  
Michèle Brocard ◽  
Nicolas Locker ◽  
Helena J. Maier
Keyword(s):  
Stress Responses ◽  
Infectious Bronchitis Virus ◽  
Cellular Stress ◽  
Stress Granules ◽  
Stress Granule ◽  
Granule Formation ◽  
Translation Machinery ◽  
Infectious Bronchitis ◽  
Eif2α Phosphorylation ◽  
Cellular Translation

AbstractViruses must hijack cellular translation machinery to efficiently express viral genes. In many cases, this is impeded by cellular stress responses. These stress responses swiftly relocate and repurpose translation machinery, resulting in global inhibition of translation and the aggregation of stalled 48S mRNPs into cytoplasmic foci called stress granules. This results in translational silencing of all mRNAs excluding those beneficial for the cell to resolve the specific stress. For example, expression of antiviral factors is maintained during viral infection. Here we investigated stress granule regulation by Gammacoronavirus infectious bronchitis virus (IBV), which causes the economically important poultry disease, infectious bronchitis. Interestingly, we found that IBV is able to inhibit multiple cellular stress granule signaling pathways whilst at the same time IBV replication also results in induction of seemingly canonical stress granules in a proportion of infected cells. Moreover, IBV infection uncouples translational repression and stress granule formation and both processes are independent of eIF2α phosphorylation. These results provide novel insights into how IBV modulates cellular translation and antiviral stress signaling.

scholarly journals THE TRANSCRIPTIONAL RESPONSE TO OXIDATIVE STRESS IS INDEPENDENT OF STRESS-GRANULE FORMATION

2021 ◽  
Author(s):  
Amanjot Singh ◽  
Arvind Reddy Kandi ◽  
Deepa Jayaprakashappa ◽  
Guillaume Thuery ◽  
Devam J Purohit ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Responses ◽  
Transcriptional Response ◽  
Stress Granules ◽  
Stress Granule ◽  
Cell Recovery ◽  
Granule Formation ◽  
Transcriptional Changes ◽  
Translational Arrest ◽  
Shock Proteins

ABSTRACTCells respond to stress with translational arrest, robust transcriptional changes, and transcription-independent formation of mRNP assemblies termed stress granules (SGs). Despite considerable interest in the role of SGs in oxidative, unfolded-protein, and viral stress responses, whether and how SGs contribute to stress-induced transcription has not been rigorously examined. To address this issue, we characterized transcriptional changes in Drosophila S2 cells induced by acute oxidative-stress and assessed how these were altered under conditions that disrupted SG assembly. Sodium-arsenite stress for 3 hours predominantly resulted in the induction or upregulation of stress-responsive mRNAs whose levels peaked during cell recovery after stress cessation. The stress-transcriptome is enriched in mRNAs coding for protein chaperones, including HSP70 and low molecular-weight heat shock proteins, glutathione transferases, and several non-coding RNAs. Oxidative stress also induced prominent cytoplasmic stress granules that disassembled 3-hours after stress cessation. As expected, RNAi-mediated knockdown of the conserved G3BP1/ Rasputin protein inhibited stress-granule assembly. However, this disruption had no significant effect on the stress-induced transcriptional response or stress-induced translational arrest. Thus, SG assembly and stress-induced effects on gene expression appear to be driven by distinctive signaling processes. We suggest that while SG assembly represents a fast, transient mechanism, the transcriptional response enables a slower, longer-lasting mechanism for adaptation to and recovery from cell stress.

scholarly journals The Herpes Simplex Virus Virion Host Shutoff Protein Enhances Translation of Viral True Late mRNAs Independently of Suppressing Protein Kinase R and Stress Granule Formation

2016 ◽  
Vol 90 (13) ◽  
pp. 6049-6057 ◽  
Author(s):  
Bianca Dauber ◽  
David Poon ◽  
Theodore dos Santos ◽  
Brett A. Duguay ◽  
Ninad Mehta ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Hela Cells ◽  
Stress Granules ◽  
Vero Cells ◽  
Stress Granule ◽  
Protein Kinase R ◽  
Viral Mrnas ◽  
Granule Formation ◽  
Simplex Virus

ABSTRACTThe herpes simplex virus (HSV) virion host shutoff (vhs) RNase destabilizes cellular and viral mRNAs, suppresses host protein synthesis, dampens antiviral responses, and stimulates translation of viral mRNAs. vhs mutants display a host range phenotype: translation of viral true late mRNAs is severely impaired and stress granules accumulate in HeLa cells, while translation proceeds normally in Vero cells. We found that vhs-deficient virus activates the double-stranded RNA-activated protein kinase R (PKR) much more strongly than the wild-type virus does in HeLa cells, while PKR is not activated in Vero cells, raising the possibility that PKR might play roles in stress granule induction and/or inhibiting translation in restrictive cells. We tested this possibility by evaluating the effects of inactivating PKR. Eliminating PKR in HeLa cells abolished stress granule formation but had only minor effects on viral true late protein levels. These results document an essential role for PKR in stress granule formation by a nuclear DNA virus, indicate that induction of stress granules is the consequence rather than the cause of the translational defect, and are consistent with our previous suggestion that vhs promotes translation of viral true late mRNAs by preventing mRNA overload rather than by suppressing eIF2α phosphorylation.IMPORTANCEThe herpes simplex virus vhs RNase plays multiple roles during infection, including suppressing PKR activation, inhibiting the formation of stress granules, and promoting translation of viral late mRNAs. A key question is the extent to which these activities are mechanistically connected. Our results demonstrate that PKR is essential for stress granule formation in the absence of vhs, but at best, it plays a secondary role in suppressing translation of viral mRNAs. Thus, the ability of vhs to promote translation of viral mRNAs can be largely uncoupled from PKR suppression, demonstrating that this viral RNase modulates at least two distinct aspects of RNA metabolism.

scholarly journals Stress Granule Formation Attenuates RACK1-Mediated Apoptotic Cell Death Induced by Morusin

2020 ◽  
Vol 21 (15) ◽  
pp. 5360
Author(s):  
Ye-Jin Park ◽  
Dong Wook Choi ◽  
Sang Woo Cho ◽  
Jaeseok Han ◽  
Siyoung Yang ◽  
...  
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Stress Granules ◽  
Protective Role ◽  
Stress Granule ◽  
Protein Kinase R ◽  
Granule Formation ◽  
Protective Function ◽  
Eif2α Phosphorylation

Stress granules are membraneless organelles composed of numerous components including ribonucleoproteins. The stress granules are characterized by a dynamic complex assembly in response to various environmental stressors, which has been implicated in the coordinated regulation of diverse biological pathways, to exert a protective role against stress-induced cell death. Here, we show that stress granule formation is induced by morusin, a novel phytochemical displaying antitumor capacity through barely known mechanisms. Morusin-mediated induction of stress granules requires activation of protein kinase R (PKR) and subsequent eIF2α phosphorylation. Notably, genetic inactivation of stress granule formation mediated by G3BP1 knockout sensitized cancer cells to morusin treatment. This protective function against morusin-mediated cell death can be attributed at least in part to the sequestration of receptors for activated C kinase-1 (RACK1) within the stress granules, which reduces caspase-3 activation. Collectively, our study provides biochemical evidence for the role of stress granules in suppressing the antitumor capacity of morusin, proposing that morusin treatment, together with pharmacological inhibition of stress granules, could be an efficient strategy for targeting cancer.

scholarly journals Infectious Bronchitis Virus Regulates Cellular Stress Granule Signaling

Viruses ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 536
Author(s):  
Matthew J. Brownsword ◽  
Nicole Doyle ◽  
Michèle Brocard ◽  
Nicolas Locker ◽  
Helena J. Maier
Keyword(s):  
Stress Responses ◽  
Infectious Bronchitis Virus ◽  
Cellular Stress ◽  
Stress Granules ◽  
Stress Granule ◽  
Granule Formation ◽  
Infectious Bronchitis ◽  
Eif2α Phosphorylation ◽  
Cellular Translation ◽  
Cellular Stress Responses

Viruses must hijack cellular translation machinery to express viral genes. In many cases, this is impeded by cellular stress responses. These stress responses result in the global inhibition of translation and the storage of stalled mRNAs, into RNA-protein aggregates called stress granules. This results in the translational silencing of the majority of mRNAs excluding those beneficial for the cell to resolve the specific stress. For example, the expression of antiviral factors is maintained during viral infection. Here we investigated stress granule regulation by Gammacoronavirus infectious bronchitis virus (IBV), which causes the economically important poultry disease, infectious bronchitis. Interestingly, we found that IBV is able to inhibit multiple cellular stress granule signaling pathways, whilst at the same time, IBV replication also results in the induction of seemingly canonical stress granules in a proportion of infected cells. Moreover, IBV infection uncouples translational repression and stress granule formation and both processes are independent of eIF2α phosphorylation. These results provide novel insights into how IBV modulates cellular translation and antiviral stress signaling.

Cell Stress Signaling Cascades Regulating Cell Fate

2018 ◽  
Vol 24 (27) ◽  
pp. 3176-3183 ◽  
Author(s):  
Rohit Gundamaraju ◽  
Ravichandra Vemuri ◽  
Wai Chin Chong ◽  
Dominic P. Geraghty ◽  
Rajaraman Eri
Keyword(s):  
Cell Death ◽  
Cell Fate ◽  
Stress Responses ◽  
Cellular Stress ◽  
Cell Stress ◽  
Signaling Cascades ◽  
Stress Signaling ◽  
Cell Type ◽  
Induce Cell Death ◽  
Stressed Cell

Initiating anti-apoptotic signaling or triggering cell death depends to a great extent on the nature or source of cellular stress and cell type. Interplay between each stress response eventually determines the fate of stressed cell. Numerous factors induce cell death by a number of pathways including apoptosis, autophagy and necrosis. Not surprisingly, some of the pathways are interrelated to each other through a mediator that could articulate the entire mechanism. The present review attempts to consolidate all the pathways included in intrinsic cellular stress such as oxidative stress and autophagy, endoplasmic reticular stress (ERS) and mitophagy and apoptosis as fate in cell stress. These stress responses are a hallmark of numerous diseases including neurodegenerative diseases, diabetes and cancer. Understanding the cross-talk between different intrinsic cell stress responses will help to develop new therapeutic targets and hence lead to the development of new therapeutics.

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