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Acetyltransferase GCN5 regulates autophagy and lysosome biogenesis by targeting TFEB

Identifieur interne : 000B17 ( Main/Exploration ); précédent : 000B16; suivant : 000B18

Acetyltransferase GCN5 regulates autophagy and lysosome biogenesis by targeting TFEB

Auteurs : Yusha Wang ; Yewei Huang ; Jiaqi Liu ; Jinna Zhang ; Mingming Xu ; Zhiyuan You ; Chao Peng ; Zhefeng Gong ; Wei Liu

Source :

EMBO Reports [ 1469-221X ] ; 2019.

RBID : PMC:6945067

Abstract

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.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945067

DOI: 10.15252/embr.201948335
PubMed: 31750630
PubMed Central: 6945067

Affiliations:

Le document en format XML

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<p>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 <italic>Drosophila</italic>
, 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 <italic>Drosophila</italic>
 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.</p>
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Acetyltransferase GCN5 regulates autophagy and lysosome biogenesis by targeting TFEB

Acetyltransferase GCN5 regulates autophagy and lysosome biogenesis by targeting TFEB

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