Modification and Reorganization of the Cytoprotective Cellular Chaperone Hsp27 during Herpes Simplex Virus Type 1 Infection

Mathew, Shomita S.; Selva, Megan P. Della; Burch, April D.

doi:10.1128/jvi.01826-08

Cited by 37 publications

(42 citation statements)

References 33 publications

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“…Hsp90α induction was observed at both low and high concentrations of bortezomib treatment of glioma and head and neck cancer cells. HSP90 has been previously shown to be important for localization of HSV polymerase to the nucleus (17), thus we hypothesized that bortezomib-induced HSP90 induction could be critical for the increased viral replication and cell killing following combination treatment. To test this hypothesis, we examined the impact of Geldanamycin, an HSP90 inhibitor, on combination treatment-induced tumor cell cytotoxicity.…”

Section: Resultsmentioning

confidence: 99%

Bortezomib-Induced Unfolded Protein Response Increases Oncolytic HSV-1 Replication Resulting in Synergistic Antitumor Effects

Yoo

Hurwitz

Bolyard

et al. 2014

Clinical Cancer Research

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Background Bortezomib is an FDA-approved proteasome inhibitor, and oncolytic HSV-1 (oHSV) is a promising therapeutic approach for cancer. We tested the impact of combining bortezomib with oHSV for anti-tumor efficacy. Methods The synergistic interaction between oHSV and bortezomib was calculated using Chou-Talalay analysis. Viral replication was evaluated using plaque assay and immune fluorescence. Western-blot assays were used to evaluate induction of ER stress and unfolded protein response (UPR). Inhibitors targeting Hsp90 were utilized to investigate the mechanism of cell killing. Anti-tumor efficacy in vivo was evaluated using subcutaneous and intracranial tumor xenografts of glioma and head and neck cancer. Survival was analyzed by Kaplan-Meier curves and two-sided log rank test. Results Combination treatment with bortezomib and oHSV, 34.5ENVE, displayed strong synergistic interaction in ovarian cancer, head & neck cancer, glioma, and malignant peripheral nerve sheath tumor (MPNST) cells. Bortezomib treatment induced ER stress, evident by strong induction of Grp78, CHOP, PERK and IRE1α (western blot analysis) and the UPR (induction of hsp40, 70 and 90). Bortezomib treatment of cells at both sublethal and lethal doses increased viral replication (p value <0.001), but inhibition of Hsp90 ablated this response, reducing viral replication and synergistic cell killing. The combination of bortezomib and 34.5ENVE significantly enhanced anti-tumor efficacy in multiple different tumor models in vivo. Conclusions The dramatic synergy of bortezomib and 34.5ENVE is mediated by bortezomib- induced UPR and warrants future clinical testing in patients.

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Section: Resultsmentioning

confidence: 99%

Bortezomib-Induced Unfolded Protein Response Increases Oncolytic HSV-1 Replication Resulting in Synergistic Antitumor Effects

Yoo

Hurwitz

Bolyard

et al. 2014

Clinical Cancer Research

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“…Cellular antioxidant chaperone Hsp27 enhances replication of the herpesvirus, most likely due to the increased oxidative stress in cells caused by viral infection (Mathew et al, 2009(Mathew et al, , 2010. The oxidative stress, one of the hallmarks of neurodegenerative diseases like AD and PD, is connected to mitochondrial dysfunction (Mancuso et al, 2010).…”

Section: Resultsmentioning

confidence: 99%

Mortalin – a multipotent chaperone regulating cellular processes ranging from viral infection to neurodegeneration

Flachbartova¹,

Kováčech²

2013

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Summary. -Heat shock 70kDa protein 9 (HSPA9)/mortalin is a heat-uninducible member of the heat shock 70 protein family. This protein has been attributed many cellular functions, including energy generation, stress response, carcinogenesis and involvement in neurodegenerative diseases, which is well documented by many names it has been given (CSA, MOT, MOT2, GRP75, PBP74, GRP-75, HSPA9B, MGC4500, MTHSP75, and mortalin). As an immortalization marker (hence the name "mortalin") in mouse embryonic fibroblasts cybrids it preferentially segregated with loss of immortality in passaged cells. Mortalin regulates the functions of the tumor suppressor protein p53 and plays important roles in stress response and maintenance of the mitochondria and endoplasmic reticulum. Furthermore, mortalin appears to have roles in membrane trafficking and viral release regulation, since it interacts with Nef protein it is necessary for secretion of exosomal negative factor (Nef) and HIV-1 virus release. Recently, mortalin has been described as a significant player in neurodegenerative diseases. Mutations in HSPA9 gene have been found in Parkinson΄s disease patients; mortalin isoform expression differs in hippocampus of patients with Alzheimer΄s disease and could regulate the β-amyloid toxicity pathway. In this review we summarize the functions of mortalin, its pathological implications in neuronal dysfunction and possible roles in neurodegenerative diseases.Keywords: HSPA9/mortalin/GRP75; mitochondria; cancer; Alzheimer΄s disease * Corresponding author: E-mail: Branislav.Kovacech@savba.sk; phone: +412-2-54788100. Abbreviations: Aβ = beta-amyloid; AD = Alzheimer΄s disease; PD = Parkinson΄s disease; HSPA9 = heat shock 70 kDa protein 9; Hsp = chaperone; MAC = membrane attack complex; Net = negative factor Contents:

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“…Hsp27 foci are distinct from and adjacent to VICE domains. In cells depleted for Hsp27, we find that virus replication is significantly reduced signifying an important, yet undefined, role for this cellular chaperone [5]. Taken together, these studies indicate that essential protein turnover decisions are made at VICE domains and that these decisions enhance virus replication, however; the role of Hsp27 in this process is unknown.…”

Section: Introductionmentioning

confidence: 99%

“…Additional studies with microinjected substrates for the 20S proteasome reveal that VICE domains are active sites of proteolysis [3]. Our lab recently reported that the antioxidant chaperone Hsp27 also forms foci in virus-infected nuclei [5]. Hsp27 foci are distinct from and adjacent to VICE domains.…”

Section: Introductionmentioning

confidence: 99%

Accumulation of oxidized proteins in Herpesvirus infected cells

Mathew

Bryant

Burch

2010

Free Radical Biology and Medicine

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Oxidative stress gives rise to an environment that can be highly damaging to proteins, lipids, and DNA. Previous studies indicate that Herpesvirus infections cause oxidative stress in cells and in tissues. The biological consequences of virus-induced oxidative stress have not been characterized. Studies from many groups indicate that proteins which have been damaged through oxidative imbalances are either degraded by the 20S proteasome in a ubiquitin-independent fashion or form aggregates that are resistant to proteolysis. We have previously shown that herpes simplex virus type 1 (HSV-1) replication was significantly enhanced in the presence of the cellular antioxidant chaperone Hsp27, indicating a possible role for this protein in managing virus-induced oxidative stress. Here we show that oxidized proteins accumulate during infections with two distantly related herpesviruses, HSV-1 and Rhesus Rhadinovirus (RRV), a close relative of the Kaposi’s sarcoma-associated herpesvirus (KSHV). The presence of oxidized proteins was not entirely unexpected as oxidative stress during herpesvirus infection has been previously documented. Unexpectedly, some oxidized proteins are removed in a proteasome-dependent fashion throughout infection and others resist degradation. Oxidized proteins that resist proteolysis become sequestered in foci within the nucleus and are not associated with virus-induced chaperone enriched domains (VICE), active centers of protein quality control, but rather coincide with Hsp27-enriched foci that were previously described by our laboratory. Experiments also indicate that the accumulation of oxidized proteins is more pronounced in cells depleted for Hsp27. We propose that Hsp27 may facilitate oxidized protein turnover at VICE domains in the nucleus during infection. Hsp27 may also buffer toxic effects of highly-carbonylated, defective proteins that resist proteolysis by promoting their aggregation in the nucleus. These roles of Hsp27 during virus infection are most likely not mutually exclusive.

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Modification and Reorganization of the Cytoprotective Cellular Chaperone Hsp27 during Herpes Simplex Virus Type 1 Infection

Cited by 37 publications

References 33 publications

Bortezomib-Induced Unfolded Protein Response Increases Oncolytic HSV-1 Replication Resulting in Synergistic Antitumor Effects

Bortezomib-Induced Unfolded Protein Response Increases Oncolytic HSV-1 Replication Resulting in Synergistic Antitumor Effects

Mortalin – a multipotent chaperone regulating cellular processes ranging from viral infection to neurodegeneration

Accumulation of oxidized proteins in Herpesvirus infected cells

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