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Deacetylation of TFEB promotes fibrillar Aß degradation by upregulating lysosomal biogenesis in microglia.
Bao, Jintao; Zheng, Liangjun; Zhang, Qi; Li, Xinya; Zhang, Xuefei; Li, Zeyang; Bai, Xue; Zhang, Zhong; Huo, Wei; Zhao, Xuyang; Shang, Shujiang; Wang, Qingsong; Zhang, Chen; Ji, Jianguo.
Afiliação
  • Bao J; State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing, 100871, China.
  • Zheng L; State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing, 100871, China.
  • Zhang Q; State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing, 100871, China.
  • Li X; State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing, 100871, China.
  • Zhang X; State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing, 100871, China.
  • Li Z; State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing, 100871, China.
  • Bai X; State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing, 100871, China.
  • Zhang Z; State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing, 100871, China.
  • Huo W; State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing, 100871, China.
  • Zhao X; Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Center for Age-Related Diseases, Peking University Health Science Center, Beijing, 100191, China.
  • Shang S; State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing, 100871, China.
  • Wang Q; State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing, 100871, China. wangqingsong@pku.edu.cn.
  • Zhang C; State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing, 100871, China. ch.zhang@pku.edu.cn.
  • Ji J; State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing, 100871, China. jijg@pku.edu.cn.
Protein Cell ; 7(6): 417-33, 2016 06.
Article em En | MEDLINE | ID: mdl-27209302
Microglia play a pivotal role in clearance of Aß 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 Aß clearance in microglia. Here we show that microglial expression of TFEB facilitates fibrillar Aß (fAß) 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 fAß 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 fAß 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 fAß degradation, making microglial activation of TFEB a possible strategy for attenuating amyloid plaque deposition in AD.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Peptídeos beta-Amiloides / Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Protein Cell Assunto da revista: BIOQUIMICA Ano de publicação: 2016 Tipo de documento: Article País de afiliação: China País de publicação: Alemanha

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Peptídeos beta-Amiloides / Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Protein Cell Assunto da revista: BIOQUIMICA Ano de publicação: 2016 Tipo de documento: Article País de afiliação: China País de publicação: Alemanha