Regulation of the transcriptome by ER stress: non-canonical mechanisms and physiological consequences

Arensdorf, Angela M.; Diedrichs, Danilo R.; Rutkowski, D. Thomas

doi:10.3389/fgene.2013.00256

Cited by 73 publications

(78 citation statements)

References 202 publications

(264 reference statements)

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“…2). This comes as no surprise, as glutamate can induce an endoplasmic reticulum stress-associated death signalling cascade in neuronal cells [28] resembling the unfolded protein response known to promote a global transcriptional reprogramming [29]. The particular finding also supports the speculation that the observed up-regulation in protein levels of these chaperones is caused probably by post-translational modifications known to block protein turnover and promote protein stability, such as ubiquitination [30], which needs further investigation.…”

Section: Discussionsupporting

confidence: 52%

Low Dose Administration of Glutamate Triggers a Non-Apoptotic, Autophagic Response in PC12 Cells

Stamoula

Vavilis

Aggelidou

et al. 2015

Cell Physiol Biochem

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Background/Aims: Increasing amounts of the neurotransmitter glutamate are associated with excitotoxicity, a phenomenon related both to homeostatic processes and neurodegenerative diseases such as multiple sclerosis. Methods: PC12 cells (rat pheochromocytoma) were treated with various concentrations of the non-essential amino acid glutamate for 0.5-24 hours. The effect of glutamate on cell morphology was monitored with electron microscopy and haematoxylin-eosin staining. Cell survival was calculated with the MTT assay. Expression analysis of chaperones associated with the observed phenotype was performed using either Western Blotting at the protein level or qRT-PCR at the mRNA level. Results: Administration of glutamate in PC12 cells in doses as low as 10 μM causes an up-regulation of GRP78, GRP94 and HSC70 protein levels, while their mRNA levels show the opposite kinetics. At the same time, GAPDH and GRP75 show reduced protein levels, irrespective of their transcriptional rate. On a cellular level, low concentrations of glutamate induce an autophagy-mediated pro-survival phenotype, which is further supported by induction of the autophagic marker LC3. Conclusion: The findings in the present study underline a discrete effect of glutamate on neuronal cell fate depending on its concentration. It was also shown that a low dose of glutamate orchestrates a unique expression signature of various chaperones and induces cell autophagy, which acts in a neuroprotective fashion.

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Section: Discussionsupporting

confidence: 52%

Low Dose Administration of Glutamate Triggers a Non-Apoptotic, Autophagic Response in PC12 Cells

Stamoula

Vavilis

Aggelidou

et al. 2015

Cell Physiol Biochem

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“…We noted similarities between the VPA transcriptional signature and that of the unfolded protein stress response (UPR)2425 (Supplementary Table S1, Table 1). The UPR reduces the load of proteins entering the endoplasmic reticulum (ER), and promotes degradation or secretion of unfolded proteins26.…”

Section: Resultsmentioning

confidence: 97%

Valproate inhibits MAP kinase signalling and cell cycle progression in S. cerevisiae

Desfossés-Baron

Hammond-Martel

Simoneau

et al. 2016

Sci Rep

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The mechanism of action of valproate (VPA), a widely prescribed short chain fatty acid with anticonvulsant and anticancer properties, remains poorly understood. Here, the yeast Saccharomyces cerevisiae was used as model to investigate the biological consequences of VPA exposure. We found that low pH strongly potentiates VPA-induced growth inhibition. Transcriptional profiling revealed that under these conditions, VPA modulates the expression of genes involved in diverse cellular processes including protein folding, cell wall organisation, sexual reproduction, and cell cycle progression. We further investigated the impact of VPA on selected processes and found that this drug: i) activates markers of the unfolded protein stress response such as Hac1 mRNA splicing; ii) modulates the cell wall integrity pathway by inhibiting the activation of the Slt2 MAP kinase, and synergizes with cell wall stressors such as micafungin and calcofluor white in preventing yeast growth; iii) prevents activation of the Kss1 and Fus3 MAP kinases of the mating pheromone pathway, which in turn abolishes cellular responses to alpha factor; and iv) blocks cell cycle progression and DNA replication. Overall, our data identify heretofore unknown biological responses to VPA in budding yeast, and highlight the broad spectrum of cellular pathways influenced by this chemical in eukaryotes.

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“…Transcripts related to GO terms ribosome biogenesis, glycosylation, sugar transport, drug export, and nuclear import were repressed. The carvacrol transcriptional signature in C. albicans was reminiscent of the unfolded protein stress response expressed in eukaryotic organisms (35,36). In response to UPR inducers such as DTT or tunicamycin, C. albicans and other fungi, including S. cerevisiae, Aspergillus niger, and Aspergillus fumigatus, activate genes involved in vesicle trafficking, protein folding, amino acid metabolism, proteolysis, glycosylation, lipid metabolism, and cell wall biogenesis (35,(37)(38)(39).…”

Section: Resultsmentioning

confidence: 99%

The Monoterpene Carvacrol Generates Endoplasmic Reticulum Stress in the Pathogenic Fungus Candida albicans

Chaillot

Tebbji

Remmal

et al. 2015

Antimicrob Agents Chemother

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The monoterpene carvacrol, the major component of oregano and thyme oils, is known to exert potent antifungal activity against the pathogenic yeast Candida albicans. This monoterpene has been the subject of a considerable number of investigations that uncovered extensive pharmacological properties, including antifungal and antibacterial effects. However, its mechanism of action remains elusive. Here, we used integrative chemogenomic approaches, including genome-scale chemical-genetic and transcriptional profiling, to uncover the mechanism of action of carvacrol associated with its antifungal property. Our results clearly demonstrated that fungal cells require the unfolded protein response (UPR) signaling pathway to resist carvacrol. The mutants most sensitive to carvacrol in our genome-wide competitive fitness assay in the yeast Saccharomyces cerevisiae expressed mutations of the transcription factor Hac1 and the endonuclease Ire1, which is required for Hac1 activation by removing a nonconventional intron from the 3= region of HAC1 mRNA. Confocal fluorescence live-cell imaging revealed that carvacrol affects the morphology and the integrity of the endoplasmic reticulum (ER). Transcriptional profiling of pathogenic yeast C. albicans cells treated with carvacrol demonstrated a bona fide UPR transcriptional signature. Ire1 activity detected by the splicing of HAC1 mRNA in C. albicans was activated by carvacrol. Furthermore, carvacrol was found to potentiate antifungal activity of the echinocandin antifungal caspofungin and UPR inducers dithiothreitol and tunicamycin against C. albicans. This comprehensive chemogenomic investigation demonstrated that carvacrol exerts its antifungal activity by altering ER integrity, leading to ER stress and the activation of the UPR to restore protein-folding homeostasis.F ungal pathogens represent a serious risk to the growing population of immunocompromised individuals resulting from the increasing success of organ and bone marrow transplantation, immune-suppressive cancer chemotherapy, premature births, and the AIDS pandemic. Candida albicans is a diploid ascomycete yeast that is an important commensal and opportunistic pathogen in humans. Systemic infections resulting from C. albicans are on the rise and are associated with mortality rates of 50% or greater despite currently available antifungal therapy (1-3). Current therapeutic options are limited to treatment with three longstanding antifungal classes, the polyenes, azoles, and echinocandins (4). These compounds target the specific fungal biological process of ergosterol metabolism (azoles and polyenes) and cell wall ␤-1,3-glucan synthesis (echinocandins). However, these drugs have serious side effects such as nephrotoxicity and/or create complications such as resistance due to their fungistatic rather than fungicidal characteristics (4-6). There is, thus, an urgent need for new strategies to identify novel protein targets and bioactive molecules for antifungal therapeutic intervention.Plants are an interesting reservoir of s...

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Regulation of the transcriptome by ER stress: non-canonical mechanisms and physiological consequences

Cited by 73 publications

References 202 publications

Low Dose Administration of Glutamate Triggers a Non-Apoptotic, Autophagic Response in PC12 Cells

Low Dose Administration of Glutamate Triggers a Non-Apoptotic, Autophagic Response in PC12 Cells

Valproate inhibits MAP kinase signalling and cell cycle progression in S. cerevisiae

The Monoterpene Carvacrol Generates Endoplasmic Reticulum Stress in the Pathogenic Fungus Candida albicans

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