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Cathepsin Inhibition-Induced Lysosomal Dysfunction Enhances Pancreatic Beta-Cell Apoptosis in High Glucose

Title
Cathepsin Inhibition-Induced Lysosomal Dysfunction Enhances Pancreatic Beta-Cell Apoptosis in High Glucose
Authors
Jung, M[Jung, Minjeong]Lee, J[Lee, Jaemeun]Seo, HY[Seo, Hye-Young]Lim, JS[Lim, Ji Sun]Kim, EK[Kim, Eun-Kyoung]
DGIST Authors
Jung, M[Jung, Minjeong]; Lee, J[Lee, Jaemeun]; Seo, HY[Seo, Hye-Young]; Lim, JS[Lim, Ji Sun]; Kim, EK[Kim, Eun-Kyoung]
Issue Date
2015-01-27
Citation
PLoS ONE, 10(1)
Type
Article
Article Type
Article
Keywords
Animal CellApoptosisAutophagyCaspase 3Caspase 9CathepsinCathepsin BCathepsin DCathepsin LCell CultureCell DeathCell FractionationCell FunctionCell ViabilityCellular DistributionControlled StudyCulture MediumDisorders of Mitochondrial FunctionsEndoplasmic Reticulum StressEnzyme ActivationEnzyme InhibitionGlucoseGlucotoxicityHyperglycemiaImmunoblottingImmunocytochemistryImmunofluorescence TestInsulinJanus KinaseLysosomeMessenger RNANon-HumanOxidative StressPancreas Islet Beta CellProtein BCL 2Protein CleavageProtein FunctionProtein ProcessingRat
ISSN
1932-6203
Abstract
Autophagy is a lysosomal degradative pathway that plays an important role in maintaining cellular homeostasis. We previously showed that the inhibition of autophagy causes pancreatic β-cell apoptosis, suggesting that autophagy is a protective mechanism for the survival of pancreatic β-cells. The current study demonstrates that treatment with inhibitors and knockdown of the lysosomal cysteine proteases such as cathepsins B and L impair autophagy, enhancing the caspase-dependent apoptosis of INS-1 cells and islets upon exposure to high concentration of glucose. Interestingly, treatment with cathepsin B and L inhibitors prevented the proteolytic processing of cathepsins B, D and L, as evidenced by gradual accumulation of the respective pro-forms. Of note, inhibition of aspartic cathepsins had no effect on autophagy and cell viability, suggesting the selective role of cathepsins B and L in the regulation of β-cell autophagy and apoptosis. Lysosomal localization of accumulated pro-cathepsins in the presence of cathepsin B and L inhibitors was verified via immunocytochemistry and lysosomal fractionation. Lysotracker staining indicated that cathepsin B and L inhibitors led to the formation of severely enlarged lysosomes in a timedependent manner. The abnormal accumulation of pro-cathepsins following treatment with inhibitors of cathepsins B and L suppressed normal lysosomal degradation and the processing of lysosomal enzymes, leading to lysosomal dysfunction. Collectively, our findings suggest that cathepsin defects following the inhibition of cathepsin B and L result in lysosomal dysfunction and consequent cell death in pancreatic β-cells. Copyright: © 2015 Jung et al.
URI
http://hdl.handle.net/20.500.11750/2611
DOI
10.1371/journal.pone.0116972
Publisher
Public Library of Science
Related Researcher
Files:
There are no files associated with this item.
Collection:
Brain and Cognitive SciencesETC1. Journal Articles


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