IRE-1 regulates cellular homeostasis during disrupted lipid metabolism

Metabolic disorders, such as non-alcoholic fatty liver disease (NAFLD), are emerging as epidemics that affect the global population. One facet of these disorders is attributed to the disturbance of membrane lipid composition. Typically activated by misfolded protein accumulation within the ER, pertu...

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Main Author: Koh, Jhee Hong
Other Authors: Guillaume Thibault
Format: Thesis-Doctor of Philosophy
Language:English
Published: Nanyang Technological University 2021
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Online Access:https://hdl.handle.net/10356/152743
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spelling sg-ntu-dr.10356-1527432023-02-28T18:39:03Z IRE-1 regulates cellular homeostasis during disrupted lipid metabolism Koh, Jhee Hong Guillaume Thibault School of Biological Sciences thibault@ntu.edu.sg Science::Biological sciences::Molecular biology Metabolic disorders, such as non-alcoholic fatty liver disease (NAFLD), are emerging as epidemics that affect the global population. One facet of these disorders is attributed to the disturbance of membrane lipid composition. Typically activated by misfolded protein accumulation within the ER, perturbation of endoplasmic reticulum (ER) homeostasis through alteration in membrane phospholipids or change in membrane lipid saturation to unsaturation ratio also activate the unfolded protein response (UPR) and cause dramatic transcriptional and translational changes in the cell. To restore cellular homeostasis, the three highly conserved UPR transducers ATF6, IRE1, and PERK mediate adaptive responses to ER stress. Understanding the differences of how lipid dysregulation causes ER perturbation is critical, as it will provide insights into the pathophysiological mechanism of metabolic diseases. Furthermore, new insights into how proteotoxic stress differs from lipid bilayer stress (LBS) may also aid in specific targeting of the UPR for a better therapeutic outcome. Our goal in this project is to establish a model system in the nematode Caenorhabditis elegans to differentiate proteotoxic stress-induced UPR and LBS-induced UPR. We evaluated sources of stress that activate UPRLBS and identified three factors that warrant further studies. These factors are (1) increased lipid unsaturation through cold stress, (2) increased lipid saturation through glucotoxicity, and (3) phosphatidylcholine (PC) deficiency through silencing of the PC biosynthesis gene phosphatidylethanolamine N-methyltransferase 2 (pmt-2). They share the common theme where perturbed cellular homeostasis caused by these factors activate IRE-1 through LBS. We show that the worms are highly responsive to PC depletion and strongly activates the UPRLBS. Hence, we focused our understanding of the UPRLBS by utilizing the PC deficiency model. Transcriptional profiling of PC-deficient worms revealed a unique subset of genes regulated in a UPR-dependent manner that is independent of proteotoxic stress. Among these, we show that autophagy is modulated through the conserved IRE-1–XBP-1 axis, strongly suggesting of the importance of autophagy in maintaining cellular homeostasis during the LBS-induced UPR. Doctor of Philosophy 2021-09-22T02:16:57Z 2021-09-22T02:16:57Z 2021 Thesis-Doctor of Philosophy Koh, J. H. (2021). IRE-1 regulates cellular homeostasis during disrupted lipid metabolism. Doctoral thesis, Nanyang Technological University, Singapore. https://hdl.handle.net/10356/152743 https://hdl.handle.net/10356/152743 10.32657/10356/152743 en This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0). application/pdf Nanyang Technological University
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Biological sciences::Molecular biology
spellingShingle Science::Biological sciences::Molecular biology
Koh, Jhee Hong
IRE-1 regulates cellular homeostasis during disrupted lipid metabolism
description Metabolic disorders, such as non-alcoholic fatty liver disease (NAFLD), are emerging as epidemics that affect the global population. One facet of these disorders is attributed to the disturbance of membrane lipid composition. Typically activated by misfolded protein accumulation within the ER, perturbation of endoplasmic reticulum (ER) homeostasis through alteration in membrane phospholipids or change in membrane lipid saturation to unsaturation ratio also activate the unfolded protein response (UPR) and cause dramatic transcriptional and translational changes in the cell. To restore cellular homeostasis, the three highly conserved UPR transducers ATF6, IRE1, and PERK mediate adaptive responses to ER stress. Understanding the differences of how lipid dysregulation causes ER perturbation is critical, as it will provide insights into the pathophysiological mechanism of metabolic diseases. Furthermore, new insights into how proteotoxic stress differs from lipid bilayer stress (LBS) may also aid in specific targeting of the UPR for a better therapeutic outcome. Our goal in this project is to establish a model system in the nematode Caenorhabditis elegans to differentiate proteotoxic stress-induced UPR and LBS-induced UPR. We evaluated sources of stress that activate UPRLBS and identified three factors that warrant further studies. These factors are (1) increased lipid unsaturation through cold stress, (2) increased lipid saturation through glucotoxicity, and (3) phosphatidylcholine (PC) deficiency through silencing of the PC biosynthesis gene phosphatidylethanolamine N-methyltransferase 2 (pmt-2). They share the common theme where perturbed cellular homeostasis caused by these factors activate IRE-1 through LBS. We show that the worms are highly responsive to PC depletion and strongly activates the UPRLBS. Hence, we focused our understanding of the UPRLBS by utilizing the PC deficiency model. Transcriptional profiling of PC-deficient worms revealed a unique subset of genes regulated in a UPR-dependent manner that is independent of proteotoxic stress. Among these, we show that autophagy is modulated through the conserved IRE-1–XBP-1 axis, strongly suggesting of the importance of autophagy in maintaining cellular homeostasis during the LBS-induced UPR.
author2 Guillaume Thibault
author_facet Guillaume Thibault
Koh, Jhee Hong
format Thesis-Doctor of Philosophy
author Koh, Jhee Hong
author_sort Koh, Jhee Hong
title IRE-1 regulates cellular homeostasis during disrupted lipid metabolism
title_short IRE-1 regulates cellular homeostasis during disrupted lipid metabolism
title_full IRE-1 regulates cellular homeostasis during disrupted lipid metabolism
title_fullStr IRE-1 regulates cellular homeostasis during disrupted lipid metabolism
title_full_unstemmed IRE-1 regulates cellular homeostasis during disrupted lipid metabolism
title_sort ire-1 regulates cellular homeostasis during disrupted lipid metabolism
publisher Nanyang Technological University
publishDate 2021
url https://hdl.handle.net/10356/152743
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