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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
Author(s)
Jung, Min JeongLee, Jae MeunSeo, Hye YoungLim, Ji SunKim, Eun Kyoung
Issued Date
2015-01
Citation
PLoS ONE, v.10, no.1
Type
Article
Keywords
CHRONIC OXIDATIVE STRESSORGANELLAR DYSFUNCTIONCYSTEINE PROTEASESIMPAIRED AUTOPHAGYSTORAGE DISEASESPROTEINLC3PATHWAYSKINASEJNK
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
  • 김은경 Kim, Eun-Kyoung 뇌과학과
  • Research Interests Neural functions in metabolic diseases; 뇌신경세포와 비만; 당뇨 등의 대사 질환 관련 연구
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Appears in Collections:
Department of Brain Sciences Lab of Neuro-Metabolism & Neurometabolomic Research Center 1. Journal Articles

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