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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, Min JeongLee, Jae MeunSeo, Hye YoungLim, Ji SunKim, Eun Kyoung
DGIST Authors
Kim, Eun Kyoung
Issued Date
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
  • 김은경 Kim, Eun-Kyoung 뇌과학과
  • Research Interests Neural functions in metabolic diseases; 뇌신경세포와 비만; 당뇨 등의 대사 질환 관련 연구
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Department of Brain Sciences Lab of Neuro-Metabolism & Neurometabolomic Research Center 1. Journal Articles


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