Lipid perturbation-activated IRE-1 modulates autophagy and lipolysis during endoplasmic reticulum stress

Koh, Jhee Hong; Wang, Lei; Beaudoin‐Chabot, Caroline; Thibault, Guillaume

doi:10.1101/285379

Cited by 3 publications

(5 citation statements)

References 114 publications

(116 reference statements)

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“…In C. elegans , ire-1 and its downstream target hsp-4 are required for fasting-induced fat droplet hydrolysis through the actions of fasting-dependent lipases [ 74 ]. Additionally, in a pmt-2 mutant with defective PC synthesis, ire-1 is required to induce lipid metabolism genes such as lipid droplet-associated lipase adipose triglyceride lipase ( atgl-1 ) [ 75 ], which is necessary for TG hydrolysis. In contrast, this activation is absent in tunicamycin-induced proteotoxic stress [ 76 ].…”

Section: Bidirectional Interplay Between Lipid Metabolism and The mentioning

confidence: 99%

Beyond Proteostasis: Lipid Metabolism as a New Player in ER Homeostasis

Taubert

2021

Metabolites

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Biological membranes are not only essential barriers that separate cellular and subcellular structures, but also perform other critical functions such as the initiation and propagation of intra- and intercellular signals. Each membrane-delineated organelle has a tightly regulated and custom-made membrane lipid composition that is critical for its normal function. The endoplasmic reticulum (ER) consists of a dynamic membrane network that is required for the synthesis and modification of proteins and lipids. The accumulation of unfolded proteins in the ER lumen activates an adaptive stress response known as the unfolded protein response (UPR-ER). Interestingly, recent findings show that lipid perturbation is also a direct activator of the UPR-ER, independent of protein misfolding. Here, we review proteostasis-independent UPR-ER activation in the genetically tractable model organism Caenorhabditis elegans. We review the current knowledge on the membrane lipid composition of the ER, its impact on organelle function and UPR-ER activation, and its potential role in human metabolic diseases. Further, we summarize the bi-directional interplay between lipid metabolism and the UPR-ER. We discuss recent progress identifying the different respective mechanisms by which disturbed proteostasis and lipid bilayer stress activate the UPR-ER. Finally, we consider how genetic and metabolic disturbances may disrupt ER homeostasis and activate the UPR and discuss how using -omics-type analyses will lead to more comprehensive insights into these processes.

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Section: Bidirectional Interplay Between Lipid Metabolism and The mentioning

confidence: 99%

Beyond Proteostasis: Lipid Metabolism as a New Player in ER Homeostasis

Taubert

2021

Metabolites

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“…RNAi clones of common genes to the reported suppressors and enhancers of glucose-induced far-3p::GFP and UPR-upregulated genes 43,45 (Fig. 4a).…”

Section: Hgd-activated Upr Regulates Longevity and Metabolism Of Wormmentioning

confidence: 99%

“…Quantitative real-time PCR (qPCR) screen was carried out as previously described with modifications 45 . Primers for qPCR are available upon request.…”

Section: Quantitative Real-time Pcrmentioning

confidence: 99%

“…Microarray data of UPR-specific genes for lipid bilayer stress (pmt-2 RNAi) and proteotoxic stress (tunicamycin) was adapted from our previous study 45 . The list of genes regulated by 2% glucose diet supplementation was kindly provided by Dr. Seung-Jae V. Lee's lab 44 .…”

Section: Computational Analysis Of Glucose-induced Upr Gene Candidatesmentioning

confidence: 99%

“…Briefly, synchronised L1 larval stage far-3p::GFP animals were grown NGM plates and harvested at 7-day-old. Five to ten M9-washed worms were seeded into 96-well microplates containing RNAi Bactria clones of previously identified HGD-modulated 44 and UPR-modulated genes 43,45 in the absence of presence of 2% glucose. Fluorescence intensity was measured by Incell 2200 Analyzer (GE Healthcare Lifesciences)…”

Section: Rnai Screeningmentioning

confidence: 99%

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Glucose increases the lifespan of post-reproductiveC. elegansindependently of FOXO

Wang

Beaudoin‐Chabot

Thibault

2018

Preprint

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Aging is one of the most critical risk factors for the development of metabolic syndromes 1 . Prominent metabolic diseases, namely type 2 diabetes and insulin resistance, have a strong association with endoplasmic reticulum (ER) stress 2 . Upon ER stress, the unfolded protein response (UPR) is activated to limit cellular damage by adapting to stress conditions and restoring ER homeostasis 3,4 . However, adaptive genes upregulated from the UPR tend to decrease with age 5 . Although stress resistance correlates with increased longevity in a variety of model organisms, the links between the UPR, ER stress resistance, and longevity remain poorly understood. Here, we show that supplementing bacteria diet with 2% glucose (high glucose diet, HGD) in post-reproductive 7-day-old (7DO) C. elegans significantly extend their lifespan in contrast to shortening the lifespan of reproductive 3-day-old (3DO) animals. The insulin-IGF receptor DAF-2 and its immediate downstream target, phosphoinositide 3-kinase (PI3K) AGE-1, were found to be critical factors in extending the lifespan of 7DO worms on HGD. The downstream transcription factor forkhead box O (FOXO) DAF-16 did not extend the lifespan of 7DO worms on HGD in contrast of its previously reported role in modulating lifespan of 3DO worms 6. Furthermore, we identified that UPR activation through the highly conserved ATF-6 and PEK-1 sensors significantly extended the longevity of 7DO worms on HGD but not through the IRE-1 sensor. Our results demonstrate that HGD extends lifespan of postreproductive worms in a UPR-dependent manner but independently of FOXO. Based on these observations, we hypothesise that HGD activates the otherwise quiescent UPR in aged worms to overcome age-related stress and to restore ER homeostasis. In contrast, young adult animals subjected to HGD leads to unresolved ER stress, conversely leading to a deleterious stress response.3

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

et al. 2019

Preprint

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

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Lipid perturbation-activated IRE-1 modulates autophagy and lipolysis during endoplasmic reticulum stress

Cited by 3 publications

References 114 publications

Beyond Proteostasis: Lipid Metabolism as a New Player in ER Homeostasis

Beyond Proteostasis: Lipid Metabolism as a New Player in ER Homeostasis

Glucose increases the lifespan of post-reproductiveC. elegansindependently of FOXO

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

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