Yaqin Sun
Xufeng Cen
Bing Shan
Qingwei Zhao
Tingxue Xie
Zhe Wang
Tingjun Hou
Yu Xue
Mengmeng Zhang
Di Peng
Qiming Sun
Cong Yi
Ayaz Najafov
Hongguang Xia
1 Department of Biochemistry&Research Center of Clinical Pharmacy of The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China;
2 Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311121, China;
3 Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA;
4 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201203, China;
5 College of Pharmaceutical Sciences, Hangzhou Institute of innovative Medicine, Zhejiang University, Hangzhou 310058, China;
6 Key Laboratory of Molecular Biophysics of Ministry of Education, Hubei Bioinformatics and Molecular Imaging Key Laboratory, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
Funds: Financial support was received from the National Key R&D Program of China (2017YFA0104200) and the National Natural Science Foundation of China (No. 91854108, 81773182 and 31601121).
Received Date: 2021-04-28
Rev Recd Date:2021-06-03
Publish Date:2021-09-27
Abstract
Abstract
Chaperone-mediated autophagy (CMA) is a lysosomedependent selective degradation pathway implicated in the pathogenesis of cancer and neurodegenerative diseases. However, the mechanisms that regulate CMA are not fully understood. Here, using unbiased drug screening approaches, we discover Metformin, a drug that is commonly the first medication prescribed for type 2 diabetes, can induce CMA. We delineate the mechanism of CMA induction by Metformin to be via activation of TAK1-IKKα/β signaling that leads to phosphorylation of Ser85 of the key mediator of CMA, Hsc70, and its activation. Notably, we find that amyloid-beta precursor protein (APP) is a CMA substrate and that it binds to Hsc70 in an IKKα/β-dependent manner. The inhibition of CMA-mediated degradation of APP enhances its cytotoxicity. Importantly, we find that in the APP/ PS1 mouse model of Alzheimer’s disease (AD), activation of CMA by Hsc70 overexpression or Metformin potently reduces the accumulated brain Aβ plaque levels and reverses the molecular and behavioral AD phenotypes. Our study elucidates a novel mechanism of CMA regulation via Metformin-TAK1-IKKα/β-Hsc70 signaling and suggests Metformin as a new activator of CMA for diseases, such as AD, where such therapeutic intervention could be beneficial.Keywords: chaperone-mediated autophagy,
Metformin,
TAK1,
IKKα/β,
Hsc70,
APP,
Alzheimer's disease
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