TFEB acetylation promotes lysosome biogenesis and ameliorates Alzheimer's disease-relevant phenotypes in mice.
TFEB acetylation promotes lysosome biogenesis and ameliorates Alzheimer's disease-relevant phenotypes in mice.
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DOI：
10.1016/j.jbc.2022.102649
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发表时间：
2022-12
影响因子：
4.8
通讯作者：
Li, Yang
中科院分区：
文献类型：
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作者：
Li, Tianyou;Yin, Limin;Kang, Xinyi;Xue, Wenlong;Wang, Ning;Zhang, Jie;Yuan, Ping;Lin, Lingxi;Li, Yang
溶酶体是调节货物降解和蛋白质质量控制的主要中心之一。转录因子EB（TFEB）促进的溶酶体生物合成增强溶酶体介导的降解和神经退行性疾病，但TFEB修饰和激活的机制仍然知之甚少。在这里，我们报告了TFEB乙酰化在TFEB核转位和溶酶体生物发生中的重要作用，这些作用独立于TFEB去磷酸化。通过筛选小分子，我们发现曲古抑菌素A（TSA），组蛋白去乙酰化酶（HDACs）的泛抑制剂，促进TFEB的核转位。TSA增强LysoTracker Red对细胞的染色，并增加溶酶体和自噬基因的表达。我们确定了四个新的乙酰化赖氨酸残基的TFEB，这是重要的TFEB核转位和溶酶体生物合成。我们表明TFEB乙酰化受到HDAC（HDAC 5、HDAC 6和HDAC 9）和赖氨酸乙酰转移酶（KAT）（包括ELP 3、CREBBP和HAT 1）的调节。在TSA诱导的TFEB胞质-细胞核易位过程中，乙酰化与TFEB去磷酸化无关，因为TFEB上的mTORC 1或GSK 3 β相关磷酸化位点仍被磷酸化。向APP/PS1小鼠施用TSA增加了小鼠脑中溶酶体和自噬基因的表达，并且还改善了记忆。因此，β-淀粉样蛋白斑块负荷降低。这些结果表明，TFEB的乙酰化，作为一种新的机制TFEB激活，促进溶酶体生物合成和阐明阿尔茨海默病的发病机制。我们的研究结果还表明，HDAC抑制可以促进溶酶体生物合成，这可能是一种潜在的治疗方法，用于治疗与HDAC过度激活相关的神经退行性疾病和障碍。
Lysosomes are one of the major centers for regulating cargo degradation and protein quality control. Transcription factor EB (TFEB)–promoted lysosome biogenesis enhances lysosome-mediated degradation and alleviates neurodegenerative diseases, but the mechanisms underlying TFEB modification and activation are still poorly understood. Here, we report essential roles of TFEB acetylation in TFEB nuclear translocation and lysosome biogenesis, which are independent of TFEB dephosphorylation. By screening small molecules, we find that Trichostatin A (TSA), the pan-inhibitor of histone deacetylases (HDACs), promotes nuclear translocation of TFEB. TSA enhances the staining of cells by LysoTracker Red and increases the expression of lysosomal and autophagic genes. We identify four novel acetylated lysine residues in TFEB, which are important for TFEB nuclear translocation and lysosome biogenesis. We show that TFEB acetylation is regulated by HDACs (HDAC5, HDAC6, and HDAC9) and lysine acetyltransferases (KATs), including ELP3, CREBBP, and HAT1. During TSA-induced cytosol-to-nucleus translocation of TFEB, acetylation is independent of TFEB dephosphorylation, since the mTORC1- or GSK3β-related phosphorylation sites on TFEB are still phosphorylated. Administration of TSA to APP/PS1 mice increases the expression of lysosomal and autophagic genes in mouse brains and also improves memory. Accordingly, the β-amyloid plaque burden is decreased. These results show that the acetylation of TFEB, as a novel mechanism of TFEB activation, promotes lysosome biogenesis and alleviates the pathogenesis of Alzheimer’s disease. Our results also suggest that HDAC inhibition can promote lysosome biogenesis, and this may be a potential therapeutic approach for the treatment of neurodegenerative diseases and disorders related to HDAC hyperactivation.
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影响因子：
18.2
作者：
Xu H;Ren D
通讯作者：
Ren D
DOI：
10.1146/annurev-cellbio-111315-125125
发表时间：
2016-10-06
影响因子：
11.3
作者：
Perera RM;Zoncu R
通讯作者：
Zoncu R
影响因子：
7.5
作者：
Ferguson SM
通讯作者：
Ferguson SM
影响因子：
14.9
作者：
Ma J;Chen T;Wu S;Yang C;Bai M;Shu K;Li K;Zhang G;Jin Z;He F;Hermjakob H;Zhu Y
通讯作者：
Zhu Y
DOI：
10.1038/nrm3565
发表时间：
2013-05
期刊：
Nature reviews. Molecular cell biology
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