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EI24 promotes cell adaption to ER stress by coordinating IRE1 signaling and calcium homeostasis.

ABSTRACT: The endoplasmic reticulum (ER) is a subcellular organelle crucial for protein folding and calcium storage. Accumulation of unfolded proteins or calcium depletion causes ER stress. Deficiency of ER stress adaptation leads to apoptosis, which is associated with several human disorders. Here, we reveal that ER transmembrane protein EI24 promotes cell adaptation to ER stress by coordinating the IRE1 branch of the unfolded protein response (UPR) and calcium signaling. Under nonstressed conditions, EI24 binds to the kinase domain of IRE1 to inhibit its activation. Upon ER stress, EI24 disassociates from IRE1 to permit UPR activation, and meanwhile targets IP3R1 to prevent ER calcium depletion, which together promote cell adaptation to ER stress. EI24 knockout causes failure of ER stress adaptation and apoptosis. Thus, EI24 is a novel anti-apoptotic factor implicated in ER stress signaling.

SUBMITTER: Xu Y

PROVIDER: S-EPMC8892245 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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EI24 promotes cell adaption to ER stress by coordinating IRE1 signaling and calcium homeostasis.

Xu Yiwei Y Chen Jie J Chen Jianguo J Teng Junlin J

EMBO reports 20220110 3

The endoplasmic reticulum (ER) is a subcellular organelle crucial for protein folding and calcium storage. Accumulation of unfolded proteins or calcium depletion causes ER stress. Deficiency of ER stress adaptation leads to apoptosis, which is associated with several human disorders. Here, we reveal that ER transmembrane protein EI24 promotes cell adaptation to ER stress by coordinating the IRE1 branch of the unfolded protein response (UPR) and calcium signaling. Under nonstressed conditions, EI ...[more]

PMID: 35005829

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EI24 promotes cell adaption to ER stress by coordinating IRE1 signaling and calcium homeostasis

Project description:The endoplasmic reticulum (ER) is a subcellular organelle crucial for protein folding and calcium storage. Accumulation of unfolded proteins or calcium depletion causes ER stress. Deficiency of ER stress adaptation leads to apoptosis, which is associated with several human disorders. Here, we reveal that ER transmembrane protein EI24 promotes cell adaptation to ER stress by coordinating the IRE1 branch of the unfolded protein response (UPR) and calcium signaling. Under non-stressed conditions, EI24 binds to the kinase domain of IRE1 to inhibit its activation. Upon ER stress, EI24 disassociates from IRE1 to permit UPR activation, and meanwhile targets IP3R1 to prevent ER calcium depletion, which together promote cell adaptation to ER stress. EI24 knockout causes failure of ER stress adaptation and apoptosis. Thus, EI24 is a novel anti-apoptotic factor implicated in ER stress signaling.

| S-SCDT-EMBOR-2020-51679V1 | biostudies-other

RCN1 suppresses ER stress-induced apoptosis via calcium homeostasis and PERK-CHOP signaling.

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Structure and Molecular Mechanism of ER Stress Signaling by the Unfolded Protein Response Signal Activator IRE1.

Project description:The endoplasmic reticulum (ER) is an important site for protein folding and maturation in eukaryotes. The cellular requirement to synthesize proteins within the ER is matched by its folding capacity. However, the physiological demands or aberrations in folding may result in an imbalance which can lead to the accumulation of misfolded protein, also known as "ER stress." The unfolded protein response (UPR) is a cell-signaling system that readjusts ER folding capacity to restore protein homeostasis. The key UPR signal activator, IRE1, responds to stress by propagating the UPR signal from the ER to the cytosol. Here, we discuss the structural and molecular basis of IRE1 stress signaling, with particular focus on novel mechanistic advances. We draw a comparison between the recently proposed allosteric model for UPR induction and the role of Hsp70 during polypeptide import to the mitochondrial matrix.

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Role of Endoplasmic Reticulum Stress Sensor IRE1? in Cellular Physiology, Calcium, ROS Signaling, and Metaflammation.

Project description:Inositol-requiring transmembrane kinase endoribonuclease-1? (IRE1?) is the most prominent and evolutionarily conserved unfolded protein response (UPR) signal transducer during endoplasmic reticulum functional upset (ER stress). A IRE1? signal pathway arbitrates yin and yang of cellular fate in objectionable conditions. It plays several roles in fundamental cellular physiology as well as in several pathological conditions such as diabetes, obesity, inflammation, cancer, neurodegeneration, and in many other diseases. Thus, further understanding of its molecular structure and mechanism of action during different cell insults helps in designing and developing better therapeutic strategies for the above-mentioned chronic diseases. In this review, recent insights into structure and mechanism of activation of IRE1? along with its complex regulating network were discussed in relation to their basic cellular physiological function. Addressing different binding partners that can modulate IRE1? function, UPRosome triggers different downstream pathways depending on the cellular backdrop. Furthermore, IRE1? are in normal cell activities outside the dominion of ER stress and activities under the weather of inflammation, diabetes, and obesity-related metaflammation. Thus, IRE1 as an ER stress sensor needs to be understood from a wider perspective for comprehensive functional meaning, which facilitates us with assembling future needs and therapeutic benefits.

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Nrf2 signaling links ER oxidative protein folding and calcium homeostasis in health and disease.

Project description:We report a signaling pathway linking two fundamental functions of the ER, oxidative protein folding, and intracellular calcium regulation. Cells sense ER oxidative protein folding through H2O2, which induces Nrf2 nuclear translocation. Nrf2 regulates the expression of GPx8, an ER glutathione peroxidase that modulates ER calcium levels. Because ER protein folding is dependent on calcium, this pathway functions as rheostat of ER calcium levels. Protein misfolding and calcium dysregulation contribute to the pathophysiology of many diseases, including amyotrophic lateral sclerosis, in which astrocytic calcium dysregulation participates in causing motor neuron death. In human-derived astrocytes harboring mutant SOD1 causative of familial amyotrophic lateral sclerosis, we show that impaired ER redox signaling decreases Nrf2 nuclear translocation, resulting in ER calcium overload and increased calcium-dependent cell secretion, leading to motor neuron death. Nrf2 activation in SOD1 mutant astrocytes with dimethyl fumarate restores calcium homeostasis and ameliorates motor neuron death. These results highlight a regulatory mechanism of intracellular calcium homeostasis by ER redox signaling and suggest that this mechanism could be a therapeutic target in SOD1 mutant astrocytes.

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Project description:IRE1, an ER-localized transmembrane protein, plays a central role in the unfolded protein response (UPR). IRE1 senses the accumulation of unfolded proteins in its luminal domain and transmits a signal to the cytosolic side through its kinase and RNase domains. Although the downstream pathways mediated by two mammalian IRE1s, IRE1? and IRE1?, are well documented, their luminal events have not been fully elucidated. In particular, there have been no reports on how IRE1? senses the unfolded proteins. In this study, we performed a comparative analysis to clarify the luminal event mediated by the mammalian IRE1s. Confocal fluorescent microscopy using GFP-fused IRE1s revealed that IRE1? clustered into discrete foci upon ER stress. Also, fluorescence correlation spectroscopy (FCS) analysis in living cells indicated that the size of the IRE1? complex is robustly increased upon ER stress. Moreover, unlike IRE1?, the luminal domain of IRE1? showed anti-aggregation activity in vitro, and IRE1? was coprecipitated with the model unfolded proteins in cells. Strikingly, association with BiP was drastically reduced in IRE1?, while IRE1? was associated with BiP and dissociated upon ER stress. This is the first report indicating that, differently from IRE1?, the luminal event mediated by IRE1? involves direct interaction with unfolded proteins rather than association/dissociation with BiP, implying an intrinsic diversity in the sensing mechanism of mammalian sensors.

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| S-EPMC5389830 | biostudies-literature

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