Stress sensor Ire1 deploys a divergent transcriptional program in response to lipid bilayer stress

Nurulain Ho; Wei Sheng Yap; Jiaming Xu; Haoxi Wu; Jhee Hong Koh; Wilson Wen Bin Goh; Bhawana George; Shu Chen Chong; Stefan Taubert; Guillaume Thibault

doi:10.1083/JCB.201909165

Stress sensor Ire1 deploys a divergent transcriptional program in response to lipid bilayer stress

Nurulain Ho, Wei Sheng Yap, Jiaming Xu, Haoxi Wu, Jhee Hong Koh, Wilson Wen Bin Goh, Bhawana George, Shu Chen Chong, Stefan Taubert, Guillaume Thibault^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

53 Citations (Scopus)

Abstract

Membrane integrity at the endoplasmic reticulum (ER) is tightly regulated, and its disturbance is implicated in metabolic diseases. Using an engineered sensor that activates the unfolded protein response (UPR) exclusively when normal ER membrane lipid composition is compromised, we identified pathways beyond lipid metabolism that are necessary to maintain ER integrity in yeast and in C. elegans. To systematically validate yeast mutants that disrupt ER membrane homeostasis, we identified a lipid bilayer stress (LBS) sensor in the UPR transducer protein Ire1, located at the interface of the amphipathic and transmembrane helices. Furthermore, transcriptome and chromatin immunoprecipitation analyses pinpoint the UPR as a broad-spectrum compensatory response wherein LBS and proteotoxic stress deploy divergent transcriptional UPR programs. Together, these findings reveal the UPR program as the sum of two independent stress responses, an insight that could be exploited for future therapeutic intervention.

Original language	English
Article number	201909165
Journal	Journal of Cell Biology
Volume	219
Issue number	7
DOIs	https://doi.org/10.1083/JCB.201909165
Publication status	Published - Jul 6 2020
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2020 Ho et al. This article is distributed under the terms of an Attribution-Noncommercial-Share Alike-No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution-Noncommercial-Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

ASJC Scopus Subject Areas

Cell Biology

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abstract = "Membrane integrity at the endoplasmic reticulum (ER) is tightly regulated, and its disturbance is implicated in metabolic diseases. Using an engineered sensor that activates the unfolded protein response (UPR) exclusively when normal ER membrane lipid composition is compromised, we identified pathways beyond lipid metabolism that are necessary to maintain ER integrity in yeast and in C. elegans. To systematically validate yeast mutants that disrupt ER membrane homeostasis, we identified a lipid bilayer stress (LBS) sensor in the UPR transducer protein Ire1, located at the interface of the amphipathic and transmembrane helices. Furthermore, transcriptome and chromatin immunoprecipitation analyses pinpoint the UPR as a broad-spectrum compensatory response wherein LBS and proteotoxic stress deploy divergent transcriptional UPR programs. Together, these findings reveal the UPR program as the sum of two independent stress responses, an insight that could be exploited for future therapeutic intervention.",

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AU - Goh, Wilson Wen Bin

AU - George, Bhawana

AU - Chong, Shu Chen

AU - Taubert, Stefan

AU - Thibault, Guillaume

N1 - Publisher Copyright: © 2020 Ho et al. This article is distributed under the terms of an Attribution-Noncommercial-Share Alike-No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution-Noncommercial-Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

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N2 - Membrane integrity at the endoplasmic reticulum (ER) is tightly regulated, and its disturbance is implicated in metabolic diseases. Using an engineered sensor that activates the unfolded protein response (UPR) exclusively when normal ER membrane lipid composition is compromised, we identified pathways beyond lipid metabolism that are necessary to maintain ER integrity in yeast and in C. elegans. To systematically validate yeast mutants that disrupt ER membrane homeostasis, we identified a lipid bilayer stress (LBS) sensor in the UPR transducer protein Ire1, located at the interface of the amphipathic and transmembrane helices. Furthermore, transcriptome and chromatin immunoprecipitation analyses pinpoint the UPR as a broad-spectrum compensatory response wherein LBS and proteotoxic stress deploy divergent transcriptional UPR programs. Together, these findings reveal the UPR program as the sum of two independent stress responses, an insight that could be exploited for future therapeutic intervention.

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Stress sensor Ire1 deploys a divergent transcriptional program in response to lipid bilayer stress

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