Volume 7 Issue 6
Jun.  2016
Turn off MathJax
Article Contents
Jintao Bao, Liangjun Zheng, Qi Zhang, Xinya Li, Xuefei Zhang, Zeyang Li, Xue Bai, Zhong Zhang, Wei Huo, Xuyang Zhao, Shujiang Shang, Qingsong Wang, Chen Zhang, Jianguo Ji. Deacetylation of TFEB promotes fibrillar Aβ degradation by upregulating lysosomal biogenesis in microglia[J]. Protein&Cell, 2016, 7(6): 417-433. doi: 10.1007/s13238-016-0269-2
Citation: Jintao Bao, Liangjun Zheng, Qi Zhang, Xinya Li, Xuefei Zhang, Zeyang Li, Xue Bai, Zhong Zhang, Wei Huo, Xuyang Zhao, Shujiang Shang, Qingsong Wang, Chen Zhang, Jianguo Ji. Deacetylation of TFEB promotes fibrillar Aβ degradation by upregulating lysosomal biogenesis in microglia[J]. Protein&Cell, 2016, 7(6): 417-433. doi: 10.1007/s13238-016-0269-2

Deacetylation of TFEB promotes fibrillar Aβ degradation by upregulating lysosomal biogenesis in microglia

doi: 10.1007/s13238-016-0269-2
Funds:

This work was supported by grants from the National Natural Science Foundation of China (Grant Nos. 31470807, 31270872, and 31200610), the National Basic Research Program (973 Program) (Nos. 2010CB912203 and 2011CB915504) and Founds from State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University.

  • Received Date: 2016-01-26
  • Rev Recd Date: 2016-03-21
  • Microglia play a pivotal role in clearance of Aβ by degrading them in lysosomes, countering amyloid plaque pathogenesis in Alzheimer's disease (AD). Recent evidence suggests that lysosomal dysfunction leads to insufficient elimination of toxic protein aggregates. We tested whether enhancing lysosomal function with transcription factor EB (TFEB), an essential regulator modulating lysosomal pathways, would promote Aβ clearance in microglia. Here we show that microglial expression of TFEB facilitates fibrillar Aβ (fAβ) degradation and reduces deposited amyloid plaques, which are further enhanced by deacetylation of TFEB. Using mass spectrometry analysis, we firstly confirmed acetylation as a previously unreported modification of TFEB and found that SIRT1 directly interacted with and deacetylated TFEB at lysine residue 116. Subsequently, SIRT1 overexpression enhanced lysosomal function and fAβ degradation by upregulating transcriptional levels of TFEB downstream targets, which could be inhibited when TFEB was knocked down. Furthermore, overexpression of deacetylated TFEB at K116R mutant in microglia accelerated intracellular fAβ degradation by stimulating lysosomal biogenesis and greatly reduced the deposited amyloid plaques in the brain slices of APP/PS1 transgenic mice. Our findings reveal that deacetylation of TFEB could regulate lysosomal biogenesis and fAβ degradation, making microglial activation of TFEB a possible strategy for attenuating amyloid plaque deposition in AD.
  • loading
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Article Metrics

    Article views (285) PDF downloads(3900) Cited by()
    Proportional views
    Related

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return