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.
Keywords: Alzheimer’s disease; TFEB; acetylation; dephosphorylation; lysosome biogenesis; ubiquitination.
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