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...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Oxford University Press
2016-05-01
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| Series: | Protein & Cell |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1007/s13238-016-0269-2 |
| _version_ | 1797711962610597888 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jintao Bao |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T07:14:47Z |
| format | Article |
| id | doaj.art-f0486a49acee4c86a4abd1ac74157ad0 |
| institution | Directory Open Access Journal |
| issn | 1674-800X 1674-8018 |
| language | English |
| last_indexed | 2024-03-12T07:14:47Z |
| publishDate | 2016-05-01 |
| publisher | Oxford University Press |
| record_format | Article |
| series | Protein & Cell |
| spelling | doaj.art-f0486a49acee4c86a4abd1ac74157ad02023-09-02T22:53:33ZengOxford University PressProtein & Cell1674-800X1674-80182016-05-017641743310.1007/s13238-016-0269-2Deacetylation of TFEB promotes fibrillar Aβ degradation by upregulating lysosomal biogenesis in microgliaJintao Bao0Liangjun Zheng1Qi Zhang2Xinya Li3Xuefei Zhang4Zeyang Li5Xue Bai6Zhong Zhang7Wei Huo8Xuyang Zhao9Shujiang Shang10Qingsong Wang11Chen Zhang12Jianguo Ji13State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking UniversityState Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking UniversityState Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking UniversityState Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking UniversityState Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking UniversityState Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking UniversityState Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking UniversityState Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking UniversityState Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking UniversityInstitute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Center for Age-Related Diseases, Peking University Health Science CenterState Key Laboratory of Biomembrane and Membrane Biotechnology, Peking UniversityState Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking UniversityState Key Laboratory of Biomembrane and Membrane Biotechnology, Peking UniversityState Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking UniversityAbstract 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.http://link.springer.com/article/10.1007/s13238-016-0269-2Alzheimer’s diseasemicroglialysosomesTFEBSIRT1deacetylation |
| spellingShingle | 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 Protein & Cell Alzheimer’s disease microglia lysosomes TFEB SIRT1 deacetylation |
| title | Deacetylation of TFEB promotes fibrillar Aβ degradation by upregulating lysosomal biogenesis in microglia |
| title_full | Deacetylation of TFEB promotes fibrillar Aβ degradation by upregulating lysosomal biogenesis in microglia |
| title_fullStr | Deacetylation of TFEB promotes fibrillar Aβ degradation by upregulating lysosomal biogenesis in microglia |
| title_full_unstemmed | Deacetylation of TFEB promotes fibrillar Aβ degradation by upregulating lysosomal biogenesis in microglia |
| title_short | Deacetylation of TFEB promotes fibrillar Aβ degradation by upregulating lysosomal biogenesis in microglia |
| title_sort | deacetylation of tfeb promotes fibrillar aβ degradation by upregulating lysosomal biogenesis in microglia |
| topic | Alzheimer’s disease microglia lysosomes TFEB SIRT1 deacetylation |
| url | http://link.springer.com/article/10.1007/s13238-016-0269-2 |
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