Dual role for CHOP in the crosstalk between autophagy and apoptosis to determine cell fate in response to amino acid deprivation

B'Chir, Wafa; Chaveroux, Cédric; Carraro, Valérie; Avérous, Julien; Maurin, Anne‐Catherine; Jousse, Céline; Muranishi, Yuki; Parry, Laurent; Fafournoux, Pierre; Bruhat, Alain

doi:10.1016/j.cellsig.2014.03.009

Cited by 96 publications

(73 citation statements)

References 32 publications

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“…[33][34][35][36][37] In this regard, recent studies have identified DDIT3 as a direct regulator of numerous genes involved in the autophagic process. [38][39][40] Here, we show that the increase of transcripts levels of several autophagy-and lysosome-related genes in colchicinetreated fish paralleled that of Ddit3 mRNA supporting these previous studies. However, the increase of lysosomal transcripts was not followed by an increase of the lysosomal function (as evidenced by the activity of CTSD), in line with the demonstrated inhibition of the autophagic flux in our samples and the recently published data showing that activation of lysosomal function depends on autophagosome-lysosome fusion.…”

Section: Discussionsupporting

confidence: 78%

Looking at the metabolic consequences of the colchicine-based in vivo autophagic flux assay

et al. 2016

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Monitoring autophagic flux in vivo or in organs remains limited and the ideal methods relative to the techniques possible with cell culture may not exist. Recently, a few papers have demonstrated the feasibility of measuring autophagic flux in vivo by intraperitoneal (IP) injection of pharmacological agents (chloroquine, leupeptin, vinblastine, and colchicine). However, the metabolic consequences of the administration of these drugs remain largely unknown. Here, we report that 0.8 mg/kg/day IP colchicine increased LC3-II protein levels in the liver of fasted trout, supporting the usefulness of this drug for studying autophagic flux in vivo in our model organism. This effect was accompanied by a decrease of plasma glucose concentration associated with a fall in the mRNA levels of gluconeogenesis-related genes. Concurrently, triglycerides and lipid droplets content in the liver increased. In contrast, transcript levels of b-oxidation-related gene Cpt1a dropped significantly. Together, these results match with the reported role of autophagy in the regulation of glucose homeostasis and intracellular lipid stores, and highlight the importance of considering these effects when using colchicine as an in vivo "autophagometer."

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Section: Discussionsupporting

confidence: 78%

Looking at the metabolic consequences of the colchicine-based in vivo autophagic flux assay

et al. 2016

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“…CHOP upregulates a number of autophagy genes but is not involved in the first steps of the autophagic process during the first 6 h of starvation (25). In addition, the present study shows that LC3-positive bodies (LC3 puncta) were not different between CHOP shRNA-transfected and untransfected cells under BFT-stimulated conditions, indicating that BFT-induced activation of CHOP may not be involved in the formation of autophagosomes.…”

Section: Discussionsupporting

confidence: 48%

“…In addition, hypoxia promotes autophagy through an HIF-1-independent pathway involving transcriptional induction of Atg5 and LC3 through the PERK-responsive transcription factors ATF4 and CHOP (28). Another study demonstrated that CHOP upregulated a number of autophagy genes during the first 6 h of starvation; however, CHOP inhibited autophagy when amino acid starvation was prolonged (25). These results suggest that CHOP plays an important role in induction or suppression of autophagy according to the stimuli.…”

Section: Discussionmentioning

confidence: 81%

Bacteroides fragilis Enterotoxin Induces Formation of Autophagosomes in Endothelial Cells but Interferes with Fusion with Lysosomes for Complete Autophagic Flux through a Mitogen-Activated Protein Kinase-, AP-1-, and C/EBP Homologous Protein-Dependent Pathway

Jeon

Myung

et al. 2017

Infect Immun

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Bacteroides fragilis enterotoxin (BFT), a virulence factor of enterotoxigenic B. fragilis (ETBF), plays an essential role in mucosal inflammation. Although autophagy contributes to the pathogenesis of diverse infectious diseases, little is known about autophagy in ETBF infection. This study was conducted to investigate the role of BFT in the autophagic process in endothelial cells (ECs). Stimulation of human umbilical vein ECs (HUVECs) with BFT increased light chain 3 protein II (LC3-II) conversion from LC3-I and protein expression of p62, Atg5, and Atg12. In addition, BFT-exposed ECs showed increased indices of autophagosomal fusion with lysosomes such as LC3-lysosome-associated protein 2 (LAMP2) colocalization and the percentage of red vesicles monitored by the expression of dual-tagged LC3B. BFT also upregulated expression of C/EBP homologous protein (CHOP), and inhibition of CHOP significantly increased indices of autophagosomal fusion with lysosomes. BFT activated an AP-1 transcription factor, in which suppression of AP-1 activity significantly downregulated CHOP and augmented autophagosomal fusion with lysosomes. Furthermore, suppression of Jun N-terminal protein kinase (JNK) mitogenactivated protein kinase (MAPK) significantly inhibited the AP-1 and CHOP signals, leading to an increase in autophagosomal fusion with lysosomes in BFT-stimulated ECs. These results suggest that BFT induced accumulation of autophagosomes in ECs, but activation of a signaling pathway involving JNK, AP-1, and CHOP may interfere with complete autophagy.KEYWORDS autophagy, Bacteroides fragilis enterotoxin, endothelial cells E nterotoxigenic Bacteroides fragilis (ETBF) is known to be associated with diarrheal diseases, inflammatory bowel diseases, and colorectal cancers. B. fragilis enterotoxin (BFT), a virulence factor of ETBF, is responsible for these diseases (1). Exposure to BFT results in the infiltration of inflammatory cells through endothelial cells (ECs) (2-4). Although aspects of pathogenesis regarding ETBF infection have been investigated, a more detailed understanding of the interaction between BFT and the host, especially BFT-induced changes in host cells, could reveal indispensable characteristics of ETBF infection.

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“…But recent studies have identified that CHOP promotes pro-survival autophagic process through the cooperation with ATF4. 37 In this study, we demonstrated that p8 acts upstream of ATF4 and CHOP in DHA-induced ER stress response in tumor cells. Although the exact p8 precise role in these mechanisms has still to be further clarified, the pro-survival autophagy induced by p8-ATF4-CHOP axis should not be ignored in cancer therapies with DHA.…”

Section: Discussionmentioning

confidence: 90%

“…The primers were as follows(forward primer and reverse primer): p8, AO staining and MDC staining Acridine orange (AO) and Dansylcadaverine (MDC) were used to evaluate the abundance of autophagic vacuoles in the cells. Following treatment, the cells were stained with AO (1 mg/ ml) or MDC (50 mM) for 15 min at 37 and subsequently examined by fluorescence microscopy.…”

Section: Srb Assaymentioning

confidence: 99%

p8 attenuates the apoptosis induced by dihydroartemisinin in cancer cells through promoting autophagy

Chen

Zeng

et al. 2015

Cancer Biology & Therapy

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Dihydroartemisinin (DHA) exhibits anticancer activities in a variety of cancer cells, but DHA alone are not effective enough for cancer therapy. In this study we found the stress-regulated protein p8 was obviously increased after DHA treatment in several cancer cells, which further to induce autophagy by the upregulation of endoplasmic reticulum stress-related protein ATF4 and CHOP. Furthermore, when we silenced p8 by siRNA in cancer cells, the apoptosis induced by DHA were notably increased, whereas the overexpression of p8 in cancer cells leaded to the resistance to DHA-induced apoptosis. Moreover, we found the inhibition of autophagy with chloroquine (CQ) can enhance the anticancer effect of DHA both in vitro and in vivo. In conclusion, we found that p8-mediated autophagy attenuates DHA-induced apoptosis in cancer cells, which provides evidence to support the use p8 as a cancer therapeutic target, and suggests that the combination treatment with DHA and autophagy inhibitor might be an effective cancer therapeutic strategy.

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Dual role for CHOP in the crosstalk between autophagy and apoptosis to determine cell fate in response to amino acid deprivation

Cited by 96 publications

References 32 publications

Looking at the metabolic consequences of the colchicine-based in vivo autophagic flux assay

Looking at the metabolic consequences of the colchicine-based in vivo autophagic flux assay

Bacteroides fragilis Enterotoxin Induces Formation of Autophagosomes in Endothelial Cells but Interferes with Fusion with Lysosomes for Complete Autophagic Flux through a Mitogen-Activated Protein Kinase-, AP-1-, and C/EBP Homologous Protein-Dependent Pathway

p8 attenuates the apoptosis induced by dihydroartemisinin in cancer cells through promoting autophagy

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