scholarly journals APOL1 risk variants cause podocytes injury through enhancing endoplasmic reticulum stress

2018 ◽  
Vol 38 (4) ◽  
Author(s):  
Hongxiu Wen ◽  
Vinod Kumar ◽  
Xiqian Lan ◽  
Seyedeh Shadafarin Marashi Shoshtari ◽  
Judith M. Eng ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Kidney Diseases ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Wild Type ◽  
Eukaryotic Translation ◽  
Risk Variants ◽  
Eukaryotic Translation Initiation ◽  
Underlying Mechanisms

Two coding sequence variants (G1 and G2) of Apolipoprotein L1 (APOL1) gene have been implicated as a higher risk factor for chronic kidney diseases (CKD) in African Americans when compared with European Americans. Previous studies have suggested that the APOL1 G1 and G2 variant proteins are more toxic to kidney cells than the wild-type APOL1 G0, but the underlying mechanisms are poorly understood. To determine whether endoplasmic reticulum (ER) stress contributes to podocyte toxicity, we generated human podocytes (HPs) that stably overexpressed APOL1 G0, G1, or G2 (Vec/HPs, G0/HPs, G1/HPs, and G2/HPs). Propidium iodide staining showed that HP overexpressing the APOL1 G1 or G2 variant exhibited a higher rate of necrosis when compared with those overexpressing the wild-type G0 counterpart. Consistently, the expression levels of nephrin and podocin proteins were significantly decreased in the G1- or G2-overexpressing cells despite the maintenance of their mRNA expressions levels. In contrast, the expression of the 78-kDa glucose-regulated protein ((GRP78), also known as the binding Ig protein, BiP) and the phosphorylation of the eukaryotic translation initiation factor 1 (eIF1) were significantly elevated in the G1/HPs and G2/HPs, suggesting a possible occurrence of ER stress in these cells. Furthermore, ER stress inhibitors not only restored nephrin protein expression, but also provided protection against necrosis in G1/HPs and G2/HPs, suggesting that APOL1 risk variants cause podocyte injury partly through enhancing ER stress.

scholarly journals Berberine Reduces Aβ42 Deposition and Tau Hyperphosphorylation via Ameliorating Endoplasmic Reticulum Stress

2021 ◽  
Vol 12 ◽  
Author(s):  
Yue Wu ◽  
Qingjie Chen ◽  
Bing Wen ◽  
Ninghua Wu ◽  
Benhong He ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Glycogen Synthase ◽  
Senile Plaques ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Pharmacological Intervention ◽  
Eukaryotic Translation ◽  
Main Component

Alzheimer’s disease (AD) is tightly related to endoplasmic reticulum stress (ER stress), which aggravates two dominant pathological manifestations of AD: senile plaques and neurofibrillary tangles. Berberine is widely applied in the clinical treatment of many diseases and is reported to have anti-AD effects. In the present study, berberine was shown to ameliorate ER stress and cognitive impairment in APP/PS1 mice. We found ER stress plays a role as a central hub for signal transduction, which was evidenced by the hyperactivation of glycogen synthase kinase 3β (GSK3β) to phosphorylate tau and the activation of PRKR-like endoplasmic reticulum kinase (PERK) subsequently to phosphorylate eukaryotic translation initiation factor-2 α (eIF2α). Also, eIF2α has regulated the expression of beta-site APP cleaving enzyme-1 (BACE1), which cleaves APP into pro-oligomerized amyloid beta 42 (Aβ42), the main component of senile plaques, proven by using siRNA targeting at eIF2α. Mechanically, berberine can reduce GSK3β activity, contributing to the downregulation of tau phosphorylation. Berberine also suppressed Aβ42 production via inhibiting the PERK/eIF2α/BACE1 signaling pathway. Taken together, these findings indicated that berberine had the potential to ameliorate two major pathological manifestations of AD mainly by suppressing ER stress. Our work provided knowledge on the pharmacological intervention of AD and the possible targets for future drug development.

scholarly journals Protein Kinase B Localization and Activation Differentially Affect S6 Kinase 1 Activity and Eukaryotic Translation Initiation Factor 4E-Binding Protein 1 Phosphorylation

1999 ◽  
Vol 19 (6) ◽  
pp. 4525-4534 ◽  
Author(s):  
Almut Dufner ◽  
Mirjana Andjelkovic ◽  
Boudewijn M. T. Burgering ◽  
Brian A. Hemmings ◽  
George Thomas
Keyword(s):  
Translation Initiation ◽  
Protein Kinase B ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Wild Type ◽  
S6 Kinase ◽  
Eukaryotic Translation ◽  
Highly Active ◽  
Eukaryotic Translation Initiation ◽  
Gsk 3Β

ABSTRACT Recent studies indicate that phosphatidylinositide-3OH kinase (PI3K)-induced S6 kinase (S6K1) activation is mediated by protein kinase B (PKB). Support for this hypothesis has largely relied on results obtained with highly active, constitutively membrane-localized alleles of wild-type PKB, whose activity is independent of PI3K. Here we set out to examine the importance of PKB signaling in S6K1 activation. In parallel, glycogen synthase kinase 3β (GSK-3β) inactivation and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) phosphorylation were monitored as markers of the rapamycin-insensitive and -sensitive branches of the PI3K signaling pathway, respectively. The results demonstrate that two activated PKBα mutants, whose basal activity is equivalent to that of insulin-induced wild-type PKB, inhibit GSK-3β to the same extent as a highly active, constitutively membrane-targeted wild-type PKB allele. However, of these two mutants, only the constitutively membrane-targeted allele of PKB induces S6K1 activation. Furthermore, an interfering mutant of PKB, which blocks insulin-induced PKB activation and GSK-3β inactivation, has no effect on S6K1 activation. Surprisingly, all the activated PKB mutants, regardless of constitutive membrane localization, induce 4E-BP1 phosphorylation and the interfering PKB mutant blocks insulin-induced 4E-BP1 phosphorylation. The results demonstrate that PKB mediates S6K1 activation only as a function of constitutive membrane localization, whereas the activation of PKB appears both necessary and sufficient to induce 4E-BP1 phosphorylation independently of its intracellular location.

scholarly journals Cell competition is driven by Xrp1-mediated phosphorylation of eukaryotic initiation factor 2α

PLoS Genetics ◽  
2021 ◽  
Vol 17 (12) ◽  
pp. e1009958
Author(s):  
Naotaka Ochi ◽  
Mai Nakamura ◽  
Rina Nagata ◽  
Naoki Wakasa ◽  
Ryosuke Nakano ◽  
...  
Keyword(s):  
Er Stress ◽  
Cell Interaction ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Bzip Transcription Factor ◽  
Cell Competition ◽  
Eukaryotic Translation ◽  
Global Protein Synthesis ◽  
Eukaryotic Translation Initiation ◽  
Dependent Cell

Cell competition is a context-dependent cell elimination via cell-cell interaction whereby unfit cells (‘losers’) are eliminated from the tissue when confronted with fitter cells (‘winners’). Despite extensive studies, the mechanism that drives loser’s death and its physiological triggers remained elusive. Here, through a genetic screen in Drosophila, we find that endoplasmic reticulum (ER) stress causes cell competition. Mechanistically, ER stress upregulates the bZIP transcription factor Xrp1, which promotes phosphorylation of the eukaryotic translation initiation factor eIF2α via the kinase PERK, leading to cell elimination. Surprisingly, our genetic data show that different cell competition triggers such as ribosomal protein mutations or RNA helicase Hel25E mutations converge on upregulation of Xrp1, which leads to phosphorylation of eIF2α and thus causes reduction in global protein synthesis and apoptosis when confronted with wild-type cells. These findings not only uncover a core pathway of cell competition but also open the way to understanding the physiological triggers of cell competition.

scholarly journals Gambogenic Acid Induces Endoplasmic Reticulum Stress in Colorectal Cancer via the Aurora A Pathway

2021 ◽  
Vol 9 ◽  
Author(s):  
Cheng Liu ◽  
Jiaxin Xu ◽  
Chenxu Guo ◽  
Xugang Chen ◽  
Chunmei Qian ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Aurora A ◽  
Eukaryotic Translation ◽  
Induced Apoptosis

Colorectal cancer (CRC) is one of the most common malignancies in the world and has a poor prognosis. In the present research, gambogenic acid (GNA), isolated from the traditional Chinese medicine gamboge, markedly induced apoptosis and inhibited the proliferation of CRC in vitro and in vivo. Furthermore, GNA triggered endoplasmic reticulum (ER) stress, which subsequently activated inositol-requiring enzyme (IRE) 1α and the eukaryotic translation initiation factor (eIF) 2α pathway. Pretreatment with salubrinal (an eIF2α inhibitor) rescued GNA-induced cell death. Furthermore, GNA downregulated the expression of Aurora A. The Aurora A inhibitor alisertib decreased ER stress. In human colorectal adenocarcinoma tissue, Aurora A was upregulated compared to normal colorectal epithelial nuclei. Furthermore, GNA ameliorated mouse colitis-associated cancer models. Our findings demonstrated that GNA significantly inhibited the proliferation of CRC through activation of ER stress by regulating Aurora A, which indicates the potential of GNA for preventing the progression of CRC.

scholarly journals Molecular docking studies of salubrinal and its analogs as inhibitors of the GADD34:PP1 enzyme

ADMET & DMPK ◽  
2019 ◽  
Vol 7 (2) ◽  
pp. 140-150 ◽  
Author(s):  
Pavlo V. Zadorozhnii ◽  
Ihor O. Pokotylo ◽  
Vadym V. Kiselev ◽  
Oxana V. Okhtina ◽  
Aleksandr V. Kharchenko
Keyword(s):  
Molecular Docking ◽  
Er Stress ◽  
Binding Site ◽  
Translation Initiation ◽  
Protein Molecule ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation Initiation Factor ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation

The phenomenon of the endoplasmic reticulum (ER) stress as a molecular pathophysiological process underlies diseases as cancer, diabetes mellitus, myocardial infarction, neurodegenerative disorders, diseases of the urinary system, disorders associated with bone integrity, etc. To prevent ER stress, salubrinal, which is a phosphatase inhibitor of the eukaryotic translation initiation factor - GADD34:PP1, is currently being intensively studied. The aim of this work is to search for new analogues of this drug using molecular docking methods. Optimization of the geometry of the studied structures and molecular docking was carried out using the ArgusLab 4.0.1 software package. The three-dimensional crystal structure of the GADD34: PP1 enzyme (PDB ID: 4XPN) was loaded in the PDB format from the protein molecule data bank. The model of the binding site was created on the basis of the phosphoric acid residue (403 PO4). The dimensions of the binding site were set manually and were 40.000 Å along the X-axis, 40.000 Å - the Y-axis and 40.000 Å - the Z-axis. The docking was done with a flexible ligand, and the semi-empirical AScore function was used for the scoring procedure. It was shown that for the salubrinal molecule the most favorable was the conformation stabilized by the intramolecular hydrogen bond formed between the hydrogen atom of the thiourea fragment and the oxygen atom of the amide fragment. According to molecular docking data, six compounds from the fifty-four analyzed analogues of salubrinal exceed it in the stability of the complex formed with GADD34:PP1. The results of this work can be used to create new phosphatase inhibitors of the eukaryotic translation initiation factor GADD34:PP1.

scholarly journals GNRH Induces the Unfolded Protein Response in the LβT2 Pituitary Gonadotrope Cell Line

2009 ◽  
Vol 23 (1) ◽  
pp. 100-112 ◽  
Author(s):  
Minh-Ha T. Do ◽  
Sharon J. Santos ◽  
Mark A. Lawson
Keyword(s):  
Er Stress ◽  
Translation Initiation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation ◽  
Unfolded Protein ◽  
Eukaryotic Translation Initiation ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Upr Pathway

The neuropeptide GNRH 1 stimulates the secretion of the reproductive hormone LH in pituitary gonadotropes. Other secretory cell types depend on the unfolded protein response (UPR) pathway to regulate protein synthesis and protect against endoplasmic reticulum (ER) stress in response to differentiation or secretory stimuli. This study investigated the role of the UPR in GNRH action within the LβT2 gonadotrope model. Cells were treated with GNRH, and the activation of UPR signaling components and general translational status was examined. The ER-resident stress sensors, Atf6, Eif2ak3, and Ern1, are all present, and GNRH stimulation results in the phosphorylation of eukaryotic translation initiation factor 2A kinase 3 and its downstream effector, eukaryotic translation initiation factor 2A. Additionally, activation of the UPR was confirmed both in LβT2 as well as mouse primary pituitary cells through identifying GNRH-induced splicing of Xbp1 mRNA, a transcription factor activated by splicing by the ER stress sensor, ER to nucleus signaling 1. Ribosome profiling revealed that GNRH stimulation caused a transient attenuation in translation, a hallmark of the UPR, remodeling ribosomes from actively translating polysomes to translationally inefficient ribonucleoprotein complexes and monosomes. The transient attenuation of specific mRNAs was also observed. Overall, the results show that GNRH activates components of the UPR pathway, and this pathway may play an important physiological role in adapting the ER of gonadotropes to the burden of their secretory demand.

scholarly journals Activation-dependent substrate recruitment by the eukaryotic translation initiation factor 2 kinase PERK

2006 ◽  
Vol 172 (2) ◽  
pp. 201-209 ◽  
Author(s):  
Stefan J. Marciniak ◽  
Lidia Garcia-Bonilla ◽  
Junjie Hu ◽  
Heather P. Harding ◽  
David Ron
Keyword(s):  
Er Stress ◽  
Translation Initiation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation Initiation Factor ◽  
Α Subunit ◽  
Eukaryotic Translation ◽  
Initiation Factor 2 ◽  
Eukaryotic Translation Initiation ◽  
Translation Initiation Factor 2

Regulated phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) by the endoplasmic reticulum (ER) stress-activated protein kinase PERK modulates protein synthesis and couples the production of ER client proteins with the organelle's capacity to fold and process them. PERK activation by ER stress is known to involve transautophosphorylation, which decorates its unusually long kinase insert loop with multiple phosphoserine and phosphothreonine residues. We report that PERK activation and phosphorylation selectively enhance its affinity for the nonphosphorylated eIF2 complex. This switch correlates with a marked change to the protease sensitivity pattern, which is indicative of a major conformational change in the PERK kinase domain upon activation. Although it is dispensable for catalytic activity, PERK's kinase insert loop is required for substrate binding and for eIF2α phosphorylation in vivo. Our findings suggest a novel mechanism for eIF2 recruitment by activated PERK and for unidirectional substrate flow in the phosphorylation reaction.

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