Adaptation to chronic ER stress enforces pancreatic β-cell plasticity

Chen, Chien-Wen; Guan, Bo‐Jhih; Alzahrani, Mohammed R.; Gao, Zhaofeng; Gao, Long; Bracey, Syrena; Wu, Jing; Mbow, Cheikh A.; Jobava, Raul; Haataja, Leena; Zalavadia, Ajay; Schaffer, Ashleigh E.; Lee, Hugo; LaFramboise, Thomas; Bederman, Ilya; Arvan, Peter; Mathews, Clayton E; Gerling, Ivan; Kaestner, Klaus H.; Tirosh, Boaz; Engin, Feyza; Hatzoglou, Maria

doi:10.1038/s41467-022-32425-7

Cited by 50 publications

(31 citation statements)

References 92 publications

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“…(3) Thirdly, multiple eIF2α kinases might be activated in neuronal cells (Alvarez-Castelao et al, 2020; Wolzak et al, 2022) during chronic ER stress, thus less susceptible to re-start an acute ISR when subsequently challenged with a different stressor, whereas glial activation of eIF2α kinases may be stimuli-specific. ISR ‘exhaustion’ has also been recently appreciated where translational-demanding cell types (in this study, pancreatic β cells) are susceptible to ATF4-mediated transcriptome decay when faced with frequent ER stress insults (Chen et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

eIF2B localisation and its regulation during the integrated stress response is cell type specific

Hanson¹,

Oliveira²,

Cross³

et al. 2023

Preprint

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Eukaryotic initiation factor 2B (eIF2B) is a master regulator of translation control. eIF2B recycles inactive eIF2-GDP to active eIF2-GTP. Under transient/acute cellular stress, a family of kinases phosphorylate the alpha subunit of eIF2 (eIF2α-P[S51]) activating the integrated stress response (ISR). This response pathway inhibits eIF2B activity resulting in overall translation attenuation and reprogramming of gene expression to overcome the stress. The duration of an ISR programme can dictate cell fate wherein chronic activation has pathological outcomes. Vanishing white matter disease (VWMD) is a chronic ISR-related disorder linked to mutations in eIF2B. eIF2B is vital to all cell types, yet VWMD eIF2B mutations primarily affect astrocytes and oligodendrocytes suggesting cell type-specific functions of eIF2B. Regulation of the cytoplasmic localisation of eIF2B (eIF2B bodies) has been implicated in the ISR. Here, we highlight the cell type specific localisation of eIF2B within neuronal and glial cell types. Our analyses revealed that each cell type possesses its own steady-state repertoire of eIF2B bodies with varied subunit composition and activity. We also demonstrate that neural and glial cell types respond similarly to acute induction of the ISR whilst a chronic ISR programme exerts cell type-specific differences. Regulatory composition of eIF2B bodies is suggested to be differentially modulated in a manner that correlates to the action of acute and chronic ISR. We also highlight a cell type specific response of the ISR inhibitor ISRIB on eIF2B localisation and activity.

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Section: Discussionmentioning

confidence: 99%

eIF2B localisation and its regulation during the integrated stress response is cell type specific

Hanson¹,

Oliveira²,

Cross³

et al. 2023

Preprint

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“…Past work has noted the importance of the endoplasmic reticulum (ER) organelle in pancreatic β cell dynamics and its stress during the physiological state, which again may influence Ca 2+ levels and impair Ca 2+dependent insulin secretion [31]. Chronic exposure to this ER stress may cause β cell exhaustion and eventually diabetes [32]. As for other metabolic-related enrichment terms, citrate cycle, aldehyde lyase, ubiquitin, and RING finger may relate to each other through mitochondria homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Characteristic comparison of human induced pluripotent stem cell-derived adult and fetal β-like cells: a differential gene expression analysis

Dany,

Nikmah,

Mariya

et al. 2023

IOP Conf. Ser.: Earth Environ. Sci.

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Differentiating human induced pluripotent stem cells (hiPSCs) into β cells for type 1 diabetes (T1D) management is a crucial step. Functionality characterization of hiPSC-derived β cells in some cases, however, only considers morphology and proliferation aspect without examining their distinct molecular properties. Thus, we aimed to investigate the difference between hiPSC-derived adult and fetal β-like cells by differentially expressed gene (DEG) analysis. We retrieved one Gene Expression Omnibus (GEO) dataset with the ID GSE70901 comprising 16 samples and GEO2RAnalyze menu performed the analysis. Network clustering was conducted through the STRING version 12.0, Cytoscape version 3.10.0, and CytoCluster 1.0 plugin by considering overall centrality parameters. Enrichment analysis was performed in DAVID 2021 and updated Enrichr tools. Two main clusters were each related to ribosome and carbohydrate metabolism. Enrichment results showed that some molecular pathways might contrast hiPSC-derived adult from fetal β-like cells, notably ribosome (p value <0.001). Cytoscape identified five significant subclusters with the densest one being ribosomal complex genes, such as RPS2, RPL5, and RPLP0 (p value <0.001). This in silico analysis provides insights into genetic signatures with their potential role in pancreatic β cell maturation, which should be validated in more thorough studies.

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“…In T1D and T2D, there is evidence of increased ER stress ( 11 , 206 ), oxidative stress ( 131 , 207 ), and autophagy ( 149 , 151 , 208 ). Although β cells can overcome acute ER stress, when overburdened, they fail to put the brakes on their stress mitigation systems and redirect themselves to destruction ( 36 ). Genetic mouse models have been key in identifying how these stress pathways contribute to β-cell dysfunction and death.…”

Section: Discussionmentioning

confidence: 99%

“…These studies report a strikingly similar trend of increased CHOP and BiP expression in islets isolated both from mice and human donors with T1D ( 11 , 12 ). In addition, islets from donors with T1D have decreased expression of genes involved in the adaptation to ER stress ( 36 ). Collectively, these studies demonstrate that β-cell ER stress is activated during the pathogenesis of T1D and may contribute to β-cell dysfunction.…”

Section: Endoplasmic Reticulum Stress In β-Cell Dysfunctionmentioning

confidence: 99%

Inside the β Cell: Molecular Stress Response Pathways in Diabetes Pathogenesis

et al. 2022

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The pathogeneses of the two major forms of diabetes, type 1 and type 2, differ with respect to their major molecular insults (loss of immune tolerance and onset of tissue insulin resistance, respectively). However, evidence suggests that dysfunction and/or death of insulin-producing β-cells is common to virtually all forms of diabetes. Although the mechanisms underlying β-cell dysfunction remain incompletely characterized, recent years have been witness to major advances in our understanding of the molecular pathways that contribute to the demise of the β-cell. Cellular and environmental factors contribute to β-cell dysfunction/loss through the activation of molecular pathways that exacerbate endoplasmic reticulum stress, the integrated stress response, oxidative stress, and impaired autophagy. Whereas many of these stress responsive pathways are interconnected, their individual contributions to glucose homeostasis and β-cell health have been elucidated through the development and interrogation of animal models. In these studies, genetic models and pharmacological compounds have enabled the identification of genes and proteins specifically involved in β-cell dysfunction during diabetes pathogenesis. Here, we review the critical stress response pathways that are activated in β-cells in the context of the animal models.

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Adaptation to chronic ER stress enforces pancreatic β-cell plasticity

Cited by 50 publications

References 92 publications

eIF2B localisation and its regulation during the integrated stress response is cell type specific

eIF2B localisation and its regulation during the integrated stress response is cell type specific

Characteristic comparison of human induced pluripotent stem cell-derived adult and fetal β-like cells: a differential gene expression analysis

Inside the β Cell: Molecular Stress Response Pathways in Diabetes Pathogenesis

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