The eIF2&amp;alpha; kinases inhibit vesicular stomatitis virus replication independently of eIF2 phosphorylation.

Krishnamoorthy, Jothilatha; Mounir, Zineb; Raven, Jennifer F.; Koromilas, Antonis E.

doi:10.4161/cc.6323

Cited by 48 publications

(53 citation statements)

References 42 publications

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“…Specifically, the ability of PERK and GCN2 to impair vesicular stomatitis virus replication in MEFs does not require eIF2a phosphorylation. 7 How the eIF2a kinases mediate their effects independently of eIF2a phosphorylation is not presently clear. One possibility is that proteins other than eIF2a can become substrates of the eIF2a kinases as has been shown for p53 21 and nuclear factors associated with dsRNA proteins.…”

Section: Discussionmentioning

confidence: 99%

“…5,6 Although eIF2a phosphorylation has a major role in mediating the biological effects of the eIF2a kinases, their ability to function independently of eIF2a phosphorylation has been reported. 7,8 Previous findings provided evidence that eIF2a phosphorylation is induced by genotoxic stress. That is, GCN2, PERK and PKR have been implicated in the DNA damage response (DDR) by various stimuli.…”

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confidence: 99%

“…5,6 Although eIF2a phosphorylation has a major role in mediating the biological effects of the eIF2a kinases, their ability to function independently of eIF2a phosphorylation has been reported. 7,8 Received 21.12.09; revised 19.5.10; accepted 19.5.10; Edited by RA Knight; published online 18.6.10 These authors contributed equally to this work. …”

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Doxorubicin bypasses the cytoprotective effects of eIF2α phosphorylation and promotes PKR-mediated cell death

et al. 2010

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The eukaryotic cell responds to various forms of environmental stress by adjusting the rates of mRNA translation thus facilitating adaptation to the assaulting stress. One of the major pathways that control protein synthesis involves the phosphorylation of the a-subunit of eukaryotic initiation factor eIF2 at serine 51. Different forms of DNA damage were shown to induce eIF2a phosphorylation by using PERK, GCN2 or PKR. However, the specificity of the eIF2a kinases and the biological role of eIF2a phosphorylation pathway in the DNA damage response (DDR) induced by chemotherapeutics are not known. Herein, we show that PKR is the eIF2a kinase that responds to DDR induced by doxorubicin. We show that activation of PKR integrates two signaling pathways with opposing biological outcomes. More specifically, induction of eIF2a phosphorylation has a cytoprotective role, whereas activation of c-jun N-terminal kinase (JNK) by PKR promotes cell death in response to doxorubicin. We further show that the proapoptotic effects of JNK activation prevail over the cytoprotection mediated by eIF2a phosphorylation. These findings reveal that PKR can be an important inducer of cell death in response to chemotherapies through its ability to act independently of eIF2a phosphorylation. The eukaryotic cell has established intricate mechanisms to cope with environmental stress. It does so by changing protein expression in a manner that promotes adaptation to the assaulting stress. Protein expression within the cell is regulated at the transcriptional, translational and posttranslational levels. Translational control is often used under conditions of cellular stress because it allows immediate and selective changes in protein levels. 1 Translation itself is divided into three distinct phases: initiation, elongation and termination. By far the most explored step is that of initiation, which has been shown to be regulated by different extracellular stimuli. 1 One of the major pathways that control translation initiation is that of the phosphorylation of the a-subunit of translation initiation factor eIF2. 2 Phosphorylation of eIF2a at serine 51 (S51) leads to the inhibition of global protein synthesis providing the cell with the opportunity to elicit adaptive responses not only by saving energy but also by preventing the accumulation of unwanted proteins that could interfere with cellular functions. 1 There are four eIF2a kinases that share a homologous kinase domain (KD) but possess different regulatory domains that enable them to become activated by distinct stimuli. 2 The eIF2a kinases are the heme-regulated inhibitor, which is found mainly in erythroid cells and is activated by heme deficiency; the endoplasmic reticulum (ER)-resident kinase (PERK), which is activated by ER stress and inhibits protein synthesis as part of the unfolded protein response; the general aminoacid nonderepressing kinase 2 (GCN2), which responds to amino-acid deprivation and becomes activated by uncharged tRNA and the RNA-dependent protein kinase PKR, an interfer...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Doxorubicin bypasses the cytoprotective effects of eIF2α phosphorylation and promotes PKR-mediated cell death

et al. 2010

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“…Both PKR and PERK are eIF2a phosphorylating kinases and eIF2a phosphorylation is required for some, 11,15 albeit not all ICD inducers, 7,11 suggesting that a certain degree of divergence in the trafficking mechanisms occurs downstream of PERK (Table 1). Intriguingly, the ability to mount an antiviral response do not always implicate eIF2a phosphorylation, 61 suggesting that other still unknown PERK-dependent mechanisms may be recruited in a ICD-dependent manner. On the other hand, UV-induced early apoptotic ecto-CRT is mediated by phosphatidylserine-based scrambling/flipping and externalization 37 ( Figure 3).…”

Section: The Plasticity and Regulation Of Danger Signalling And Sensingmentioning

confidence: 99%

Danger signalling during cancer cell death: origins, plasticity and regulation

et al. 2013

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Accumulating data indicates that following anti-cancer treatments, cancer cell death can be perceived as immunogenic or tolerogenic by the immune system. The former is made possible due to the ability of certain anti-cancer modalities to induce immunogenic cell death (ICD) that is associated with the emission of damage-associated molecular patterns (DAMPs), which assist in unlocking a sequence of events leading to the development of anti-tumour immunity. In response to ICD inducers, activation of endoplasmic reticulum (ER) stress has been identified to be indispensable to confer the immunogenic character of cancer cell death, due to its ability to coordinate the danger signalling pathways responsible for the trafficking of vital DAMPs and subsequent anti-cancer immune responses. However, in recent times, certain processes apart from ER stress have emerged (e.g., autophagy and possibly viral response-like signature), which have the ability to influence danger signalling. In this review, we discuss the molecular nature, emerging plasticity in the danger signalling mechanisms and immunological impact of known DAMPs in the context of immunogenic cancer cell death. We also discuss key effector mechanisms modulating the interface between dying cancer cells and the immune cells, which we believe are crucial for the therapeutic relevance of ICD in the context of human cancers, and also discuss the influence of experimental conditions and animal models on these. The ultimate outcome of an immune response to cancer cell death (i.e., anti-tumourigenic, pro-tumourigenic or autoimmunity or different combinations of these) tends to be complex and may depend on a number of factors like the type of the cancer cells that die and their in vivo location, the type of cell death pathway they follow to die, the types of immune cells that phagocytose them or interact with them and, last but not the least, whether a cancer antigen is recognized or not. Tolerogenicity towards cell death, as happens predominantly when cancer cells undergo physiological apoptosis (after treatment with most anti-cancer therapies), depends on a number of factors including the presence of immunosuppressive factors, absence or inactivation of DAMPs, induction of tolerogenic dendritic cells (DCs), 'suboptimal' activation of CD8 þ T cells only and apoptotic 'mimicry'.Accentuated immunogenicity exhibited by cancer cells undergoing immunogenic cell death (ICD; after treatment with selected anti-cancer therapies), depends on a number of factors like emission of DAMPs (i.e., surface exposure of certain chaperones, secretion or release of certain nucleotides and endokines), presence of immunostimulatory factors, induction of DC maturation (both phenotypic and functional) and optimal activation of CD4 þ ab, CD8 þ ab and gd T-cell responses. Certain DAMPs are actively trafficked during ICD by danger signalling pathways, which are instigated and regulated by a complex interplay between endoplasmic reticulum (ER) stress, reactive oxygen species (ROS) production and cert...

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“…The role of GCN2 in controlling viral infection has been previously demonstrated with vesicular stomatitis virus, and infection with Sinbis virus has been shown to lead to eIF2␣ phosphorylation (22,24). Given the anti-viral potential of GCN2 and its role in phosphorylating eIF2␣, we wanted to determine whether GCN2 also contributed to early phosphorylation of eIF2␣ during DENV-2 infection.…”

Section: Figure 1 Denv-2 Infectivity Of 2ftgh Cells and Induction Ofmentioning

confidence: 99%

Dengue Virus Modulates the Unfolded Protein Response in a Time-dependent Manner

Peña

Harris

2011

Journal of Biological Chemistry

170

203

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Flaviviruses, such as dengue virus (DENV), depend on the host endoplasmic reticulum for translation, replication, and packaging of their genomes. Here we report that DENV-2 infection modulates the unfolded protein response in a time-dependent manner. We show that early DENV-2 infection triggers and then suppresses PERK-mediated eIF2␣ phosphorylation and that in mid and late DENV-2 infection, the IRE1-XBP1 and ATF6 pathways are activated, respectively. Activation of IRE1-XBP1 correlated with induction of downstream targets GRP78, CHOP, and GADD34. Furthermore, induction of CHOP did not induce apoptotic markers, such as suppression of anti-apoptotic protein Bcl-2, activation of caspase-9 or caspase-3, and cleavage of poly(ADPribose) polymerase. Finally, we show that DENV-2 replication is affected in PERK ؊/؊ and IRE1 ؊/؊ mouse embryo fibroblasts when compared with wild-type mouse embryo fibroblasts. These results demonstrate that time-dependent activation of the unfolded protein response by DENV-2 can override inhibition of translation, prevent apoptosis, and prolong the viral life cycle.

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The eIF2α kinases inhibit vesicular stomatitis virus replication independently of eIF2 phosphorylation.

Cited by 48 publications

References 42 publications

Doxorubicin bypasses the cytoprotective effects of eIF2α phosphorylation and promotes PKR-mediated cell death

Doxorubicin bypasses the cytoprotective effects of eIF2α phosphorylation and promotes PKR-mediated cell death

Danger signalling during cancer cell death: origins, plasticity and regulation

Dengue Virus Modulates the Unfolded Protein Response in a Time-dependent Manner

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