scholarly journals Dual leucine zipper kinase-dependent PERK activation contributes to neuronal degeneration following insult

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Martin Larhammar ◽  
Sarah Huntwork-Rodriguez ◽  
Zhiyu Jiang ◽  
Hilda Solanoy ◽  
Arundhati Sengupta Ghosh ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Leucine Zipper ◽  
Neuronal Degeneration ◽  
Stress Signaling ◽  
Jnk Signaling ◽  
Activating Transcription Factor 4 ◽  
Activating Transcription Factor ◽  
Transcription Factor 4 ◽  
Neuronal Stress

The PKR-like endoplasmic reticulum kinase (PERK) arm of the Integrated Stress Response (ISR) is implicated in neurodegenerative disease, although the regulators and consequences of PERK activation following neuronal injury are poorly understood. Here we show that PERK signaling is a component of the mouse MAP kinase neuronal stress response controlled by the Dual Leucine Zipper Kinase (DLK) and contributes to DLK-mediated neurodegeneration. We find that DLK-activating insults ranging from nerve injury to neurotrophin deprivation result in both c-Jun N-terminal Kinase (JNK) signaling and the PERK- and ISR-dependent upregulation of the Activating Transcription Factor 4 (ATF4). Disruption of PERK signaling delays neurodegeneration without reducing JNK signaling. Furthermore, DLK is both sufficient for PERK activation and necessary for engaging the ISR subsequent to JNK-mediated retrograde injury signaling. These findings identify DLK as a central regulator of not only JNK but also PERK stress signaling in neurons, with both pathways contributing to neurodegeneration.

Endoplasmic reticulum stress induced by hepatitis B virus X protein enhances cyclo-oxygenase 2 expression via activating transcription factor 4

2011 ◽  
Vol 435 (2) ◽  
pp. 431-439 ◽  
Author(s):  
Hyun Kook Cho ◽  
Kyu Jin Cheong ◽  
Hye Young Kim ◽  
JaeHun Cheong
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Critical Role ◽  
Activating Transcription Factor 4 ◽  
B Virus ◽  
Activating Transcription Factor ◽  
Transcription Factor 4 ◽  
Cox2 Expression

Chronic hepatitis B is a disease of the liver that can progress to cirrhosis and liver cancer. The HBx (hepatitis B virus X) protein of hepatitis B virus is a multifunctional regulator that induces ER (endoplasmic reticulum) stress by previously unknown mechanisms. ER stress plays a critical role in inflammatory induction and COX2 (cyclo-oxygenase 2) is an important mediator of this inflammation. In the present study, we demonstrate the molecular mechanisms of HBx on induction of ER stress and COX2 expression. In addition, HBx reduced expression of enzymes which are involved in mitochondrial β-oxidation of fatty acids and the mitochondrial inner membrane potential. The reduction in intracellular ATP levels by HBx induced the unfolded protein response and COX2 expression through the eIF2α (eukaryotic initiation factor 2α)/ATF4 (activating transcription factor 4) pathway. We confirmed that ATF4 binding to the COX2 promoter plays a critical role in HBx-mediated COX2 induction. The results of the present study suggest that HBV infection contributes to induction of hepatic inflammation through dysfunction of cellular organelles including the ER and mitochondria.

FGF19 (fibroblast growth factor 19) as a novel target gene for activating transcription factor 4 in response to endoplasmic reticulum stress

2013 ◽  
Vol 450 (1) ◽  
pp. 221-229 ◽  
Author(s):  
Makoto Shimizu ◽  
Juan Li ◽  
Ryuto Maruyama ◽  
Jun Inoue ◽  
Ryuichiro Sato
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Growth Factor ◽  
Endoplasmic Reticulum Stress ◽  
Fibroblast Growth ◽  
Activating Transcription Factor 4 ◽  
Fgf19 Expression ◽  
Activating Transcription Factor ◽  
Fibroblast Growth Factor 19 ◽  
Transcription Factor 4

FGF19 (fibroblast growth factor 19), expressed in the small intestine, acts as an enterohepatic hormone by mediating inhibitory effects on the bile acid synthetic pathway and regulating carbohydrate and lipid metabolism. In an attempt to identify novel agents other than bile acids that induce increased FGF19 expression, we found that some ER (endoplasmic reticulum) stress inducers were effective. When intestinal epithelial Caco-2 cells were incubated with thapsigargin, marked increases were observed in the mRNA and secreted protein levels of FGF19. This was not associated with the farnesoid X receptor. Reporter gene analyses using the 5′-promoter region of FGF19 revealed that a functional AARE (amino-acid-response element) was localized in this region, and this site was responsible for inducing its transcription through ATF4 (activating transcription factor 4), which is activated in response to ER stress. EMSAs (electrophoretic mobility-shift assays) and ChIP (chromatin immunoprecipitation) assays showed that ATF4 bound to this site and enhanced FGF19 expression. Overexpression of ATF4 in Caco-2 cells induced increased FGF19 mRNA expression, whereas shRNA (short hairpin RNA)-mediated depletion of ATF4 significantly attenuated a thapsigargin-induced increase in FGF19 mRNA.

scholarly journals Combined Transcriptomic and Proteomic Analysis of Perk Toxicity Pathways

2021 ◽  
Vol 22 (9) ◽  
pp. 4598
Author(s):  
Rebeka Popovic ◽  
Ivana Celardo ◽  
Yizhou Yu ◽  
Ana C. Costa ◽  
Samantha H. Y. Loh ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Calcium Signalling ◽  
Nucleotide Metabolism ◽  
Protein Kinase R ◽  
Unfolded Protein ◽  
Activating Transcription Factor 4 ◽  
Activating Transcription Factor ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Transcription Factor 4

In Drosophila, endoplasmic reticulum (ER) stress activates the protein kinase R-like endoplasmic reticulum kinase (dPerk). dPerk can also be activated by defective mitochondria in fly models of Parkinson’s disease caused by mutations in pink1 or parkin. The Perk branch of the unfolded protein response (UPR) has emerged as a major toxic process in neurodegenerative disorders causing a chronic reduction in vital proteins and neuronal death. In this study, we combined microarray analysis and quantitative proteomics analysis in adult flies overexpressing dPerk to investigate the relationship between the transcriptional and translational response to dPerk activation. We identified tribbles and Heat shock protein 22 as two novel Drosophila activating transcription factor 4 (dAtf4) regulated transcripts. Using a combined bioinformatics tool kit, we demonstrated that the activation of dPerk leads to translational repression of mitochondrial proteins associated with glutathione and nucleotide metabolism, calcium signalling and iron-sulphur cluster biosynthesis. Further efforts to enhance these translationally repressed dPerk targets might offer protection against Perk toxicity.

scholarly journals Targeting the Integrated Stress Response in Cancer Therapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaobing Tian ◽  
Shengliang Zhang ◽  
Lanlan Zhou ◽  
Attila A. Seyhan ◽  
Liz Hernandez Borrero ◽  
...  
Keyword(s):  
Stress Response ◽  
Cancer Therapy ◽  
Integrated Stress Response ◽  
Eif2α Phosphorylation ◽  
Activating Transcription Factor 4 ◽  
Cellular Apoptosis ◽  
Dependent Protein ◽  
Pathway Regulation ◽  
Activating Transcription Factor ◽  
Transcription Factor 4

The integrated stress response (ISR) is an evolutionarily conserved intra-cellular signaling network which is activated in response to intrinsic and extrinsic stresses. Various stresses are sensed by four specialized kinases, PKR-like ER kinase (PERK), general control non-derepressible 2 (GCN2), double-stranded RNA-dependent protein kinase (PKR) and heme-regulated eIF2α kinase (HRI) that converge on phosphorylation of serine 51 of eIF2α. eIF2α phosphorylation causes a global reduction of protein synthesis and triggers the translation of specific mRNAs, including activating transcription factor 4 (ATF4). Although the ISR promotes cell survival and homeostasis, when stress is severe or prolonged the ISR signaling will shift to regulate cellular apoptosis. We review the ISR signaling pathway, regulation and importance in cancer therapy.

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