PERK Signaling Regulates Extracellular Proteostasis of an Amyloidogenic Protein During Endoplasmic Reticulum Stress

Romine, Isabelle C.; Wiseman, R. Luke

doi:10.1038/s41598-018-37207-0

Cited by 20 publications

(21 citation statements)

References 45 publications

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“…A recent study shows that the amyloidogenic protein, transthyretin, undergoes aggregation under Tg plus PERK inhibition 17 . We blotted the cell extracts under nonreducing conditions to investigate whether sERr is also associated with formation of aggregates.…”

Section: Resultsmentioning

confidence: 99%

Pharmacological induction of selective endoplasmic reticulum retention as a strategy for cancer therapy

et al. 2020

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The integrated stress response (ISR) converges on eIF2α phosphorylation to regulate protein synthesis. ISR is activated by several stress conditions, including endoplasmic reticulum (ER) stress, executed by protein kinase R-like endoplasmic reticulum kinase (PERK). We report that ER stress combined with ISR inhibition causes an impaired maturation of several tyrosine kinase receptors (RTKs), consistent with a partial block of their trafficking from the ER to the Golgi. Other proteins mature or are secreted normally, indicating selective retention in the ER (sERr). sERr is relieved upon protein synthesis attenuation and is accompanied by the generation of large mixed disulfide bonded complexes, including ERp44. sERr was pharmacologically recapitulated by combining the HIV-protease inhibitor nelfinavir with ISRIB, an experimental drug that inhibits ISR. Nelfinavir/ISRIB combination is highly effective to inhibit the growth of RTK-addicted cell lines and hepatocellular (HCC) cells in vitro and in vivo. Thus, pharmacological sERr can be utilized as a modality for cancer treatment.

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Section: Resultsmentioning

confidence: 99%

Pharmacological induction of selective endoplasmic reticulum retention as a strategy for cancer therapy

et al. 2020

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“…Under our conditions, we examined whether ER stress was involved in the effects of ZEN on BAEC apoptosis. It has been known that when ER stress is induced, the phosphorylation of PERK is increased, which then activates the PERK/eIF2α-dependent pro-apoptotic transcriptional signal to induce apoptosis [29,30]. For this reason, we chose the level of phosphorylation of PERK as a marker of ER stress.…”

Section: The Endoplasmic Reticulum (Er) Is the Organelle Responsible mentioning

confidence: 99%

Zearalenone Induces Endothelial Cell Apoptosis through Activation of a Cytosolic Ca2+/ERK1/2/p53/Caspase 3 Signaling Pathway

Lee

2021

Toxins

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Zearalenone (ZEN) is a mycotoxin that has been reported to damage various types of cells/tissues, yet its effects on endothelial cells (ECs) have never been investigated. Therefore, this study investigates the potential effects of ZEN using bovine aortic ECs (BAECs). In this study, we found that ZEN induced apoptosis of BAECs through increased cleavage of caspase 3 and poly ADP-ribose polymerase (PARP). ZEN also increased phosphorylation of ERK1/2 and p53, and treatment with the ERK1/2 or p53 inhibitor reversed ZEN-induced EC apoptosis. Transfection of BAECs with small interfering RNA against ERK1/2 or p53 revealed ERK1/2 as an upstream target of p53 in ZEN-stimulated apoptosis. ZEN increased the production of reactive oxygen species (ROS), yet treatment with the antioxidant did not prevent EC apoptosis. Similarly, blocking of estrogen receptors by specific inhibitors also did not prevent ZEN-induced apoptosis. Finally, chelation of cytosolic calcium (Ca2+) using BAPTA-AM or inhibition of endoplasmic reticulum (ER) Ca2+ channel using 2-APB reversed ZEN-induced EC apoptosis, but not by inhibiting ER stress using 4-PBA. Together, our findings demonstrate that ZEN induces EC apoptosis through an ERK1/2/p53/caspase 3 signaling pathway activated by Ca2+ release from the ER, and this pathway is independent of ROS production and estrogen receptor activation.

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“…The increase in mir-26a-5p was targeted to the EIF2AK3 (PERK) gene ( Figure 7B and Supplementary Table 4 ). PERK-dependent ATF4 activation induces the expression of stress-sensitive genes responsible for cellular redox potential and apoptosis signaling ( Romine and Wiseman, 2019 ). Upregulated mir-26a-5p targets the gene PERK and may aim to suppress antioxidant protection and activate apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Analysis of miRNAs Profiles in Serum of Patients With Steatosis and Steatohepatitis

Vulf

Skuratovskaia

Komar

et al. 2021

Front. Cell Dev. Biol.

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Non-alcoholic fatty liver disease (NAFLD) is emerging as one of the most common chronic liver diseases worldwide, affecting 25% of the world population. In recent years, there has been increasing evidence for the involvement of microRNAs in the epigenetic regulation of genes taking part in the development of steatosis and steatohepatitis—two main stages of NAFLD pathogenesis. In the present study, miRNA profiles were studied in groups of patients with steatosis and steatohepatitis to compare the characteristics of RNA-dependent epigenetic regulation of the stages of NAFLD development. According to the results of miRNA screening, 23 miRNAs were differentially expressed serum in a group of patients with steatohepatitis and 2 in a group of patients with steatosis. MiR-195-5p and miR-16-5p are common differentially expressed miRNAs for both steatosis and steatohepatitis. We analyzed the obtained results: the search for target genes for the differentially expressed miRNAs in our study and the subsequent gene set enrichment analysis performed on KEGG and REACTOME databases revealed which metabolic pathways undergo changes in RNA-dependent epigenetic regulation in steatosis and steatohepatitis. New findings within the framework of this study are the dysregulation of neurohumoral pathways in the pathogenesis of NAFLD as an object of changes in RNA-dependent epigenetic regulation. The miRNAs differentially expressed in our study were found to target 7% of genes in the classic pathogenesis of NAFLD in the group of patients with steatosis and 50% in the group of patients with steatohepatitis. The effects of these microRNAs on genes for the pathogenesis of NAFLD were analyzed in detail. MiR-374a-5p, miR-1-3p and miR-23a-3p do not target genes directly involved in the pathogenesis of NAFLD. The differentially expressed miRNAs found in this study target genes largely responsible for mitochondrial function. The role of miR-423-5p, miR-143-5p and miR-200c-3 in regulating apoptotic processes in the liver and hepatocarcinogenesis is of interest for future experimental studies. These miR-374a, miR-143, miR-1, miR-23a, and miR-423 have potential for steatohepatitis diagnosis and are poorly studied in the context of NAFLD. Thus, this work opens up prospects for further studies of microRNAs as diagnostic and therapeutic biomarkers for NAFLD.

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PERK Signaling Regulates Extracellular Proteostasis of an Amyloidogenic Protein During Endoplasmic Reticulum Stress

Cited by 20 publications

References 45 publications

Pharmacological induction of selective endoplasmic reticulum retention as a strategy for cancer therapy

Pharmacological induction of selective endoplasmic reticulum retention as a strategy for cancer therapy

Zearalenone Induces Endothelial Cell Apoptosis through Activation of a Cytosolic Ca2+/ERK1/2/p53/Caspase 3 Signaling Pathway

Analysis of miRNAs Profiles in Serum of Patients With Steatosis and Steatohepatitis

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