title: Deacetylation of TFEB promotes fibrillar Aβ degradation by upregulating lysosomal biogenesis in microglia.
abstract: 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.
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing, 100871, China.
authors.forename: Jintao
authors.initials: J
authors.lastname: Bao
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing, 100871, China.
authors.forename: Liangjun
authors.initials: L
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing, 100871, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing, 100871, China.
authors.forename: Xinya
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing, 100871, China.
authors.forename: Xuefei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing, 100871, China.
authors.forename: Zeyang
authors.initials: Z
authors.lastname: Li
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing, 100871, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Bai
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing, 100871, China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing, 100871, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Huo
authors.affiliation: 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.
authors.forename: Xuyang
authors.initials: X
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing, 100871, China.
authors.forename: Shujiang
authors.initials: S
authors.lastname: Shang
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing, 100871, China. wangqingsong@pku.edu.cn.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing, 100871, China. ch.zhang@pku.edu.cn.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing, 100871, China. jijg@pku.edu.cn.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Ji
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D010455:Peptides / Q000032:analysis / Q000737:chemistry; D011485:Protein Binding; D034622:RNA Interference; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D018118:Chloride Channels; D010455:Peptides; C064972:TFEB protein, human; D056564:Sirtuin 1
keywords: Alzheimer’s disease; SIRT1; TFEB; deacetylation; lysosomes; microglia