Membrane lipid saturation activates <scp>IRE</scp>1α without inducing clustering

Kitai, Yuto; Ariyama, Hiroyuki; Kono, Nozomu; Oikawa, Daisuke; Iwawaki, Takao; Arai, Hiroyuki

doi:10.1111/gtc.12074

Cited by 81 publications

(75 citation statements)

References 61 publications

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“…Recent findings have revealed regulatory relationships between lipid biology, ER homeostasis, and disease pathogenesis (12,13,19,21,22,38). Through the study of a lipid regulator, the Mediator subunit MDT-15, we now show that membrane lipid composition can directly influence the circuit that senses ER homeostasis.…”

Section: Discussionmentioning

confidence: 87%

“…Last, mdt-15(RNAi) worms, but not SCD(RNAi) worms, also display increased C16:0 in PC, likely because of mdt-15's requirement for fat-5 expression [fat-5 catalyzes the conversion of C16:0 to C16:1 (41)]. Exogenous C16:0 induces the UPR ER in various cell lines (12,22,42,43) and thus might explain the residual UPR ER in mdt-15 worms. Alternatively, it is possible that the combination of FA changes remaining in supplemented mdt-15(RNAi) worms underlies the residual UPR ER induction.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, in yeast, in cultured mammalian cells, and in mice, ER membrane disequilibrium also activates the UPR ER ; because chemical chaperones, which improve protein-folding capacity in the ER, alleviate UPR ER induction in these contexts, it is likely that these lipid alterations indirectly affect ER proteostasis (19,20). However, recent evidence suggests that IRE1 and PERK retain the ability to activate the UPR ER even without a functional unfolded protein sensing domain (21,22), indicating that membrane lipid perturbations directly activate the UPR ER . In this study, we set out to dissect mdt-15's role in FA homeostasis.…”

Section: Significancementioning

confidence: 99%

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Activation of the endoplasmic reticulum unfolded protein response by lipid disequilibrium without disturbed proteostasis in vivo

Hou

Gutschmidt

Choi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

165

190

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The Mediator is a conserved transcriptional coregulator complex required for eukaryotic gene expression. In Caenorhabditis elegans, the Mediator subunit mdt-15 is essential for the expression of genes involved in fatty acid metabolism and ingestion-associated stress responses. mdt-15 loss of function causes defects in reproduction and mobility and shortens lifespan. In the present study, we find that worms with mutated or depleted mdt-15 (mdt-15 worms) exhibit decreased membrane phospholipid desaturation, especially in phosphatidylcholine. Accordingly, mdt-15 worms exhibit disturbed endoplasmic reticulum (ER) homeostasis, as indicated by a constitutively activated ER unfolded protein response (UPR ER ). Activation of this stress response is only partially the consequence of reduced membrane lipid desaturation, implicating other mdt-15-regulated processes in maintaining ER homeostasis. Interestingly, mdt-15 inactivation or depletion of the lipid metabolism enzymes stearoyl-CoA-desaturases (SCD) and S-adenosyl methionine synthetase (sams-1) activates the UPR ER without promoting misfolded protein aggregates. Moreover, these worms exhibit wild-type sensitivity to chemically induced protein misfolding, and they do not display synthetic lethality with mutations in UPR ER genes, which cause protein misfolding. Therefore, the constitutively activated UPR ER in mdt-15, SCD, and sams-1 worms is not the consequence of proteotoxic stress but likely is the direct result of changes in ER membrane fluidity and composition. Together, our data suggest that the UPR ER is induced directly upon membrane disequilibrium and thus monitors altered ER homeostasis.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

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Activation of the endoplasmic reticulum unfolded protein response by lipid disequilibrium without disturbed proteostasis in vivo

Hou

Gutschmidt

Choi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

165

190

View full text Add to dashboard Cite

show abstract

“…Furthermore, IRE1α and PERK can directly induce fatty acid, phospholipid, and cholesterol biosynthetic pathways (21,95), likely to safeguard intracellular membrane homeostasis. Intriguingly, it was recently reported that the IRE1α and PERK transmembrane regions can sense saturated fatty acid accumulation and stiffening of the ER membrane (96), though surprisingly without concomitant IRE1α foci formation (97). UPR activation, and RIDD in particular, is therefore likely highly attuned to the intensity and nature of the extracellular stressor.…”

Section: Lipid Metabolismmentioning

confidence: 98%

Endoplasmic Reticulum Stress in Immunity

Bettigole

Glimcher

2015

Annu. Rev. Immunol.

398

330

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Immune responses occur in the midst of a variety of cellular stresses that can severely perturb endoplasmic reticulum (ER) function. The unfolded protein response is a three-pronged signaling axis dedicated to preserving ER homeostasis. In this review, we highlight many important and emerging functional roles for ER stress in immunity, focusing on how the bidirectional cross talk between immunological processes and basic cell biology leads to pleiotropic signaling outcomes and enhanced sensitivity to inflammatory stimuli. We also discuss how dysregulated ER stress responses can provoke many diseases, including autoimmunity, firmly positioning the unfolded protein response as a major therapeutic target in human disease.

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“…Recent findings suggest that ER lipid perturbation can trigger the UPR directly and independently of luminal accumulation of unfolded proteins. The mechanisms through which the UPR is activated by accumulating unfolded proteins and membrane lipid saturation turned out to be different as the latter does not involve large protein cluster formation in the ER membrane [70] . Two of the ER stress receptors, IRE1α and PERK have been revealed to respond to increased lipid saturation.…”

Section: Lipotoxic Er Stressmentioning

confidence: 99%

Lipotoxicity in the liver

Zámbó

Simon-Szabó

Szelényi

et al. 2013

WJH

164

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Obesity due to excessive food intake and the lack of physical activity is becoming one of the most serious public health problems of the 21 st century. With the increasing prevalence of obesity, non-alcoholic fatty liver disease is also emerging as a pandemic. While previously this pathophysiological condition was mainly attributed to triglyceride accumulation in hepatocytes, recent data show that the development of oxidative stress, lipid peroxidation, cell death, inflammation and fibrosis are mostly due to accumulation of fatty acids, and the altered composition of membrane phospholipids. In fact, triglyceride accumulation might play a protective role, and the higher toxicity of saturated or trans fatty acids seems to be the consequence of a blockade in triglyceride synthesis. Increased membrane saturation can profoundly disturb cellular homeostasis by impairing the function of membrane receptors, channels and transporters. However, it also induces endoplasmic reticulum stress via novel sensing mechanisms of the organelle's stress receptors. The triggered signaling pathways in turn largely contribute to the development of insulin resistance and apoptosis. These findings have substantiated the lipotoxic liver injury hypothesis for the pathomechanism of hepatosteatosis. This minireview focuses on the metabolic and redox aspects of lipotoxicity and lipoapoptosis, with special regards on the involvement of endoplasmic reticulum stress responses. Key words: Saturated fatty acid; Lipotoxicity; Steatosis; Lipoapoptosis; Endoplasmic reticulum stress Core tip: Surplus of free fatty acids contributes to hepatic injuries in obesity and type 2 diabetes. Intracellular accumulation of fatty acyl-CoA causes oxidative and endoplasmic reticulum (ER) stress, which lead to cell death, inflammation and fibrosis. Steatohepatosis is the consequence of an intensive fat synthesis, aiming to reduce the metabolic burden. The higher toxicity of saturated vs unsaturated fatty acids is partly due to a limited capacity of the liver cells to insert them into triglycerides. Moreover, increased membrane saturation triggers the ER stress response though a unique mechanism, which aggravates the metabolic derangements and liver injuries.

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Membrane lipid saturation activates IRE1α without inducing clustering

Cited by 81 publications

References 61 publications

Activation of the endoplasmic reticulum unfolded protein response by lipid disequilibrium without disturbed proteostasis in vivo

Activation of the endoplasmic reticulum unfolded protein response by lipid disequilibrium without disturbed proteostasis in vivo

Endoplasmic Reticulum Stress in Immunity

Lipotoxicity in the liver

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