Endoplasmic reticulum stress and pancreatic β-cell death

Fonseca, Sonya G.; Gromada, Jesper; Urano, Fumihiko

doi:10.1016/j.tem.2011.02.008

Cited by 283 publications

(322 citation statements)

References 99 publications

(117 reference statements)

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“…We therefore considered the possibility that the unfolded protein response may be involved in the transfer of granules. In our culture assay, during the several hours of culture of DCs with beta cells, we did not find up-regulation in the expression of any of the ER stress sensors: We evaluated a panel of canonical ER stress markers that are highly transcriptionally up-regulated during ER stress responses (27,28) (Fig. S1 shows one representative result).…”

Section: Significancementioning

confidence: 88%

Beta cells transfer vesicles containing insulin to phagocytes for presentation to T cells

Vomund

Zinselmeyer

Hughes

et al. 2015

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

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Beta cells from nondiabetic mice transfer secretory vesicles to phagocytic cells. The passage was shown in culture studies where the transfer was probed with CD4 T cells reactive to insulin peptides. Two sets of vesicles were transferred, one containing insulin and another containing catabolites of insulin. The passage required live beta cells in a close cell contact interaction with the phagocytes. It was increased by high glucose concentration and required mobilization of intracellular Ca 2+ . Live images of beta cell-phagocyte interactions documented the intimacy of the membrane contact and the passage of the granules. The passage was found in beta cells isolated from islets of young nonobese diabetic (NOD) mice and nondiabetic mice as well as from nondiabetic humans. Ultrastructural analysis showed intraislet phagocytes containing vesicles having the distinct morphology of dense-core granules. These findings document a process whereby the contents of secretory granules become available to the immune system. autoimmune diabetes | autoimmunity | insulin reactivity | insulin-reactive T cells

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Section: Significancementioning

confidence: 88%

Beta cells transfer vesicles containing insulin to phagocytes for presentation to T cells

Vomund

Zinselmeyer

Hughes

et al. 2015

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

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“…These proteins detect the accumulation of unfolded proteins in the ER lumen and activate mechanisms to restore its homeostasis [3][4][5]. In unresolved ER stress, persistent stimulation of the UPR triggers apoptosis via activation of C/EBP homologous protein (CHOP), c-jun N-terminal kinase (JNK), death protein 5 (DP5) and other proapoptotic signals [6,7].…”

Section: Introductionmentioning

confidence: 99%

Cytokines induce endoplasmic reticulum stress in human, rat and mouse beta cells via different mechanisms

et al. 2015

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Aims/hypothesis Proinflammatory cytokines contribute to beta cell damage in type 1 diabetes in part through activation of endoplasmic reticulum (ER) stress. In rat beta cells, cytokineinduced ER stress involves NO production and consequent inhibition of the ER Ca 2+ transporting ATPase sarco/ endoplasmic reticulum Ca 2+ pump 2 (SERCA2B). However, the mechanisms by which cytokines induce ER stress and apoptosis in mouse and human pancreatic beta cells remain unclear. The purpose of this study is to elucidate the role of ER stress on cytokine-induced beta cell apoptosis in these three species and thus solve ongoing controversies in the field. Methods Rat and mouse insulin-producing cells, human pancreatic islets and human EndoC-βH1 cells were exposed to the cytokines IL-1β, TNF-α and IFN-γ, with or without NO inhibition. A global comparison of cytokine-modulated gene expression in human, mouse and rat beta cells was also performed. The chemical chaperone tauroursodeoxycholic acid (TUDCA) and suppression of C/EBP homologous protein (CHOP) were used to assess the role of ER stress in cytokineinduced apoptosis of human beta cells. Results NO plays a key role in cytokine-induced ER stress in rat islets, but not in mouse or human islets. Bioinformatics analysis indicated greater similarity between human and mouse than between human and rat global gene expression after cytokine exposure. The chemical chaperone TUDCA and suppression of CHOP or c-Jun N-terminal kinase (JNK) protected human beta cells against cytokine-induced apoptosis. Conclusions/interpretation These observations clarify previous results that were discrepant owing to the use of islets from different species, and confirm that cytokine-induced ER stress contributes to human beta cell death, at least in part via JNK activation.

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“…Four members of BH3-only family, BBC3, PMAIP1, BID, and BCL2L11, mediate apoptosis triggered by ER stress (18, 20 -22). In addition, BBC3, PMAIP1, BCL2L11, and TNFRSF10B are regulated by DDIT3 (18,21,23), which is an ER stress-inducible gene and a key mediator of ER stress-induced apoptosis in many cell types including murine fibroblast cells (24), lymphocyte cells (25), and pancreatic ␤ cells (26).…”

mentioning

confidence: 99%

DDIT3 and KAT2A Proteins Regulate TNFRSF10A and TNFRSF10B Expression in Endoplasmic Reticulum Stress-mediated Apoptosis in Human Lung Cancer Cells

Lei

et al. 2015

Journal of Biological Chemistry

104

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Background:The mechanisms of transcriptional regulation of TNFRSF10A and TNFRSF10B are not well described. Results: DDIT3 and KAT2A cooperatively up-regulated TNFRSF10A and TNFRSF10B. Conclusion: DDIT3 and KAT2A promote the transcription of TNFRSF10A and TNFRSF10B via the AP-1 and DDIT3 binding sites, respectively. Significance: Our findings offer new insights on the mechanisms of ER stress-mediated apoptosis.

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Endoplasmic reticulum stress and pancreatic β-cell death

Cited by 283 publications

References 99 publications

Beta cells transfer vesicles containing insulin to phagocytes for presentation to T cells

Beta cells transfer vesicles containing insulin to phagocytes for presentation to T cells

Cytokines induce endoplasmic reticulum stress in human, rat and mouse beta cells via different mechanisms

DDIT3 and KAT2A Proteins Regulate TNFRSF10A and TNFRSF10B Expression in Endoplasmic Reticulum Stress-mediated Apoptosis in Human Lung Cancer Cells

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