Effects of ER stress on unfolded protein responses, cell survival, and viral replication in primary effusion lymphoma

Shigemi, Zenpei; Baba, Yusuke; Hara, Naoko; Matsuhiro, Jumpei; Kagawa, Hiroyasu; Watanabe, Tadashi; Fujimuro, Masahiro

doi:10.1016/j.bbrc.2015.12.032

Cited by 18 publications

(20 citation statements)

References 22 publications

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“…6A), another ER stressor known to promote gammaherpesvirus reactivation from latency 5,6 . As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Viral reactivation can be induced upon appropriate stimuli that are usually cytotoxic 3 , although herpesvirus lytic proteins may partially counteract their cytotoxic effects. ER stress is one of the stimuli able to induce the reactivation from latency of KSHV 4,5 and EBV 6 , two gammaherpesviruses strictly associated to Primary Effusion Lymphoma (PEL) and endemic Burkitt’s lymphoma (eBL), respectively. Endoplasmic Reticulum (ER) stress, triggered by perturbations within the ER that alter protein folding and processing, leads to the activation of the unfolded protein response (UPR) 7 .…”

Section: Introductionmentioning

confidence: 99%

“…The underlying mechanisms of the ER stress-mediated gammaherpesvirus reactivation from latency are not fully clarified yet. Activating factor 4 (ATF4) and X-box binding protein 1 (XBP1) have been shown to be involved in KSHV replication induced by several ER stressors 5 . Conversely, in another study, IRE1α and PERK, ER stress sensors, is shown to be down regulated in PEL cells during the latent phase.…”

Section: Introductionmentioning

confidence: 99%

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Bortezomib promotes KHSV and EBV lytic cycle by activating JNK and autophagy

Granato

Romeo

Tiano

et al. 2017

Sci Rep

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KSHV and EBV are gammaherpesviruses strictly linked to human cancers. Even if the majority of cancer cells harbor a latent infection, the few cells that undergo viral replication may contribute to the pathogenesis and maintenance of the virus-associated malignancies. Cytotoxic drugs used for the therapies of cancers harboring virus-infection often have, as side effect, the activation of viral lytic cycle. Therefore it is important to investigate whether they affect viral reactivation and understand the underlying mechanisms involved. In this study, we found that proteasome inhibitor bortezomib, a cytotoxic drug that efficiently target gammaherpesvirus-associated B cell lymphomas, triggered KSHV or EBV viral lytic cycle by activating JNK, in the course of ER stress, and inducing autophagy. These results suggest that the manipulation of these pathways could limit viral spread and improve the outcome of bortezomib treatment in patients affected by gammaherpesvirus-associated lymphomas.

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“…6A), another ER stressor known to promote gammaherpesvirus reactivation from latency 5,6 . As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Bortezomib promotes KHSV and EBV lytic cycle by activating JNK and autophagy

Granato

Romeo

Tiano

et al. 2017

Sci Rep

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“…Thapsigargin (TG) is a classic ER stress inducer that can initiate the stress condition in different cells [24]. When cells are exposed to TG, ER stress can be induced through inhibiting Ca2+-ATPase transporters at the ER membrane [25], which results in apoptosis when the degree of endoplasmic reticulum stress is overwhelming [26].…”

Section: Resultsmentioning

confidence: 99%

Valproate Attenuates Endoplasmic Reticulum Stress-Induced Apoptosis in SH-SY5Y Cells via the AKT/GSK3β Signaling Pathway

Xie

et al. 2017

IJMS

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Endoplasmic reticulum (ER) stress-induced apoptosis plays an important role in a range of neurological disorders, such as neurodegenerative diseases, spinal cord injury, and diabetic neuropathy. Valproate (VPA), a typical antiepileptic drug, is commonly used in the treatment of bipolar disorder and epilepsy. Recently, VPA has been reported to exert neurotrophic effects and promote neurite outgrowth, but its molecular mechanism is still unclear. In the present study, we investigated whether VPA inhibited ER stress and promoted neuroprotection and neuronal restoration in SH-SY5Y cells and in primary rat cortical neurons, respectively, upon exposure to thapsigargin (TG). In SH-SY5Y cells, cell viability was detected by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and the expression of ER stress-related apoptotic proteins such as glucose‑regulated protein (GRP78), C/EBP homologous protein (CHOP), and cleaved caspase-12/-3 were analyzed with Western blot analyses and immunofluorescence assays. To explore the pathway involved in VPA-induced cell proliferation, we also examined p-AKT, GSK3β, p-JNK and MMP-9. Moreover, to detect the effect of VPA in primary cortical neurons, immunofluorescence staining of β-III tubulin and Anti-NeuN was analyzed in primary cultured neurons exposed to TG. Our results demonstrated that VPA administration improved cell viability in cells exposed to TG. In addition, VPA increased the levels of GRP78 and p-AKT and decreased the levels of ATF6, XBP-1, GSK3β, p-JNK and MMP-9. Furthermore, the levels of the ER stress-induced apoptosis response proteins CHOP, cleaved caspase-12 and cleaved caspase-3 were inhibited by VPA treatment. Meanwhile, VPA administration also increased the ratio of Bcl-2/Bax. Moreover, VPA can maintain neurite outgrowth of primary cortical neurons. Collectively, the neurotrophic effect of VPA is related to the inhibition of ER stress-induced apoptosis in SH-SY5Y cells and the maintenance of neuronal growth. Collectively, our results suggested a new approach for the therapeutic function of VPA in neurological disorders and neuroprotection.

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“…There is supporting evidence that excessive UPR signaling inhibits KSHV lytic replication. Strong pharmacologic induction of the UPR with 2-deoxyglucose, brefeldin A, tunicamycin, or treatment with ER stress-inducing proteasome inhibitors (bortezomib, MG132, lactacystin, proteasome inhibitor I) can induce lytic reactivation while inhibiting virion production and triggering apoptosis [140][141][142][143]. We speculate that the virus may induce low levels of UPR activation to remodel the host cell and promote efficient lytic replication, but acute ER stress may still be detrimental to the virus due to the ensuing terminal pro-apoptotic UPR.…”

Section: Gammaherpesviruses and The Uprmentioning

confidence: 99%

Herpesviruses and the Unfolded Protein Response

Johnston

McCormick

2019

Viruses

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Herpesviruses usurp cellular stress responses to promote viral replication and avoid immune surveillance. The unfolded protein response (UPR) is a conserved stress response that is activated when the protein load in the ER exceeds folding capacity and misfolded proteins accumulate. The UPR aims to restore protein homeostasis through translational and transcriptional reprogramming; if homeostasis cannot be restored, the UPR switches from "helper" to "executioner", triggering apoptosis. It is thought that the burst of herpesvirus glycoprotein synthesis during lytic replication causes ER stress, and that these viruses may have evolved mechanisms to manage UPR signaling to create an optimal niche for replication. The past decade has seen considerable progress in understanding how herpesviruses reprogram the UPR. Here we provide an overview of the molecular events of UPR activation, signaling and transcriptional outputs, and highlight key evidence that herpesviruses hijack the UPR to aid infection.

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Effects of ER stress on unfolded protein responses, cell survival, and viral replication in primary effusion lymphoma

Cited by 18 publications

References 22 publications

Bortezomib promotes KHSV and EBV lytic cycle by activating JNK and autophagy

Bortezomib promotes KHSV and EBV lytic cycle by activating JNK and autophagy

Valproate Attenuates Endoplasmic Reticulum Stress-Induced Apoptosis in SH-SY5Y Cells via the AKT/GSK3β Signaling Pathway

Herpesviruses and the Unfolded Protein Response

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