Antioxidants Complement the Requirement for Protein Chaperone Function to Maintain β-Cell Function and Glucose Homeostasis

Diabetes
Jaeseok HanRandal J Kaufman

Abstract

Proinsulin misfolding in the endoplasmic reticulum (ER) initiates a cell death response, although the mechanism(s) remains unknown. To provide insight into how protein misfolding may cause β-cell failure, we analyzed mice with the deletion of P58(IPK)/DnajC3, an ER luminal co-chaperone. P58(IPK-/-) mice become diabetic as a result of decreased β-cell function and mass accompanied by induction of oxidative stress and cell death. Treatment with a chemical chaperone, as well as deletion of Chop, improved β-cell function and ameliorated the diabetic phenotype in P58(IPK-/-) mice, suggesting P58(IPK) deletion causes β-cell death through ER stress. Significantly, a diet of chow supplemented with antioxidant dramatically and rapidly restored β-cell function in P58(IPK-/-) mice and corrected abnormal localization of MafA, a critical transcription factor for β-cell function. Antioxidant feeding also preserved β-cell function in Akita mice that express mutant misfolded proinsulin. Therefore defective protein folding in the β-cell causes oxidative stress as an essential proximal signal required for apoptosis in response to ER stress. Remarkably, these findings demonstrate that antioxidant feeding restores cell function upon deletion of an...Continue Reading

References

Sep 15, 1999·Proceedings of the National Academy of Sciences of the United States of America·Y TanakaR P Robertson
Feb 6, 2004·The Journal of Cell Biology·Benjamin P Tu, Jonathan S Weissman
Aug 12, 2006·The Journal of Pharmacology and Experimental Therapeutics·Jin Yan, Barbara F Hales
Jun 15, 2007·Molecular Biology of the Cell·D Thomas RutkowskiRamanujan S Hegde
Jul 27, 2007·Journal of Medicinal Food·Soo-Hyun KimSeung-Shi Ham
Nov 6, 2007·Antioxidants & Redox Signaling·Jyoti D Malhotra, Randal J Kaufman
Feb 21, 2008·Molecular & Cellular Proteomics : MCP·Om V SinghPamela L Zeitlin
Nov 18, 2008·Proceedings of the National Academy of Sciences of the United States of America·Jyoti D MalhotraRandal J Kaufman
Sep 15, 2009·Trends in Endocrinology and Metabolism : TEM·R Paul Robertson
Feb 25, 2010·Science Signaling·Decio L Eizirik, Miriam Cnop
Mar 3, 2011·Nature Cell Biology·Ira Tabas, David Ron
May 11, 2011·Proceedings of the National Academy of Sciences of the United States of America·Ann-Hwee LeeLaurie H Glimcher
Mar 27, 2012·Annual Review of Biochemistry·Sung Hoon Back, Randal J Kaufman
Jun 27, 2012·The Journal of Cell Biology·Shiyu Wang, Randal J Kaufman
Oct 4, 2012·Nature Cell Biology·Katleen Lemaire, Frans Schuit
Apr 3, 2014·Biochimica Et Biophysica Acta·Randal J Kaufman, Jyoti D Malhotra

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Citations

Oct 22, 2015·Neural Regeneration Research·Todd McLaughlin, Sarah X Zhang
Oct 16, 2015·PLoS Biology·Justin R HasslerRandal J Kaufman
May 6, 2016·Journal of Lipid Research·Jaeseok Han, Randal J Kaufman
Jan 30, 2018·Annals of the New York Academy of Sciences·Anoop ArunagiriPeter Arvan
Dec 6, 2017·The Journal of Endocrinology·Mohammed BensellamD Ross Laybutt
Sep 20, 2018·Diabetes, Obesity & Metabolism·Yael RiahiGil Leibowitz
Sep 20, 2018·Diabetes, Obesity & Metabolism·Ming LiuPeter Arvan
Nov 20, 2018·Antioxidants & Redox Signaling·Petr JežekLydie Plecitá-Hlavatá
Feb 22, 2018·The Biochemical Journal·Stanley M H ChanTerence P Herbert
Oct 21, 2016·Pflügers Archiv : European journal of physiology·Chrysovalantou MihailidouHippokratis Kiaris
Feb 24, 2016·Molecular Endocrinology·T GurloP C Butler
Jan 1, 2015·Healthcare·Qiuhua Shen, Janet D Pierce
Jun 22, 2019·Current Protein & Peptide Science·Zhi ZhengBingdong Sha
May 17, 2018·International Journal of Molecular Medicine·Sirikul KulanuwatNattachet Plengvidhya
Sep 25, 2018·Frontiers in Aging Neuroscience·Todd McLaughlinSarah Xin Zhang
Oct 22, 2019·Journal of Molecular Biology·Leticia P Roma, Jean-Christophe Jonas
Mar 7, 2021·Ageing Research Reviews·Abdoulaye DianeMohammed Dehbi
Jun 25, 2021·Nature Reviews. Endocrinology·Jing YongRandal J Kaufman
Jun 18, 2021·JCI Insight·Sneha SitaramanTimothy E Weaver
Aug 7, 2021·Cell Death Discovery·Lea Daverkausen-Fischer, Felicitas Pröls

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Methods Mentioned

BETA
protein-folding
protein folding
light microscopy
Transmission
ELISA
PCR

Software Mentioned

ImageJ

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis