Accumulating evidence highlights the role of histone acetyltransferase GCN5 in the regulation of cell metabolism in metazoans. Here, we report that GCN5 is a negative regulator of autophagy, a lysosome-dependent catabolic mechanism. In animal cells and Drosophila, GCN5 inhibits the biogenesis of autophagosomes and lysosomes by targeting TFEB, the master transcription factor for autophagy- and lysosome-related gene expression. We show that GCN5 is a specific TFEB acetyltransferase, and acetylation by GCN5 results in the decrease in TFEB transcriptional activity. Induction of autophagy inactivates GCN5, accompanied by reduced TFEB acetylation and increased lysosome formation. We further demonstrate that acetylation at K274 and K279 disrupts the dimerization of TFEB and the binding of TFEB to its target gene promoters. In a Tau-based neurodegenerative Drosophila model, deletion of dGcn5 improves the clearance of Tau protein aggregates and ameliorates the neurodegenerative phenotypes. Together, our results reveal GCN5 as a novel conserved TFEB regulator, and the regulatory mechanisms may be involved in autophagy- and lysosome-related physiological and pathological processes.

中文翻译：

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乙酰转移酶 GCN5 通过靶向 TFEB 调节自噬和溶酶体生物发生。

越来越多的证据强调了组蛋白乙酰转移酶 GCN5 在调节后生动物细胞代谢中的作用。在这里，我们报告 GCN5 是自噬的负调节因子，自噬是一种依赖溶酶体的分解代谢机制。在动物细胞和果蝇中，GCN5 通过靶向 TFEB（自噬和溶酶体相关基因表达的主要转录因子）来抑制自噬体和溶酶体的生物合成。我们表明 GCN5 是一种特异性 TFEB 乙酰转移酶，GCN5 的乙酰化导致 TFEB 转录活性降低。自噬的诱导使 GCN5 失活，伴随着 TFEB 乙酰化减少和溶酶体形成增加。我们进一步证明 K274 和 K279 的乙酰化破坏了 TFEB 的二聚化和 TFEB 与其靶基因启动子的结合。在基于 Tau 的神经退行性果蝇模型中，dGcn5 的缺失改善了 Tau 蛋白聚集体的清除并改善了神经退行性表型。总之，我们的结果揭示了 GCN5 作为一种新型保守的 TFEB 调节剂，其调节机制可能涉及自噬和溶酶体相关的生理和病理过程。