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

Cathepsin Inhibition-Induced Lysosomal Dysfunction Enhances Pancreatic Beta-Cell Apoptosis in High Glucose
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
PLoS ONE, 10(1)
Article Type
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
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.
Public Library of Science
Related Researcher
  • Author Kim, Eun Kyoung Lab of Neuro-Metabolism & Neurometabolomic Research Center
  • Research Interests Neural functions in metabolic diseases; 뇌신경세포와 비만; 당뇨 등의 대사 질환 관련 연구
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Department of Brain and Cognitive SciencesLab of Neuro-Metabolism & Neurometabolomic Research Center1. Journal Articles

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