Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy

Li, Xinjian; Yu, Willie; Qian, Xu; Xia, Yan; Zheng, Yanhua; Lee, Jong Ho; Li, Wei; Lyu, Jianxin; Rao, Ganesh; Zhang, Xiaochun; Qian, Chao Nan; Rozen, Steven G.; Jiang, Tao; Lu, Zhimin

doi:10.1016/j.molcel.2017.04.026

Cited by 268 publications

(273 citation statements)

References 54 publications

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“…5). Very recently, it was reported that AMPK-dependent phosphorylation of the lipogenic enzyme ACSS2 induced its translocation to the nucleus, where it stimulated TFEB-dependent gene expression 204 . ACSS2 has been hypothesized to control the local synthesis of acetyl- CoA pools in the nucleus to control acetylation of his-tones and other transcriptional regulators 205 (FIG.…”

Section: Ampk Regulates Autophagy and Mitophagymentioning

confidence: 99%

AMPK: guardian of metabolism and mitochondrial homeostasis

Herzig

Shaw

2017

Nat Rev Mol Cell Biol

2,750

2,008

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Cells constantly adapt their metabolism to meet their energy needs and respond to nutrient availability. Eukaryotes have evolved a very sophisticated system to sense low cellular ATP levels via the serine/threonine kinase AMP-activated protein kinase (AMPK) complex. Under conditions of low energy, AMPK phosphorylates specific enzymes and growth control nodes to increase ATP generation and decrease ATP consumption. In the past decade, the discovery of numerous new AMPK substrates has led to a more complete understanding of the minimal number of steps required to reprogramme cellular metabolism from anabolism to catabolism. This energy switch controls cell growth and several other cellular processes, including lipid and glucose metabolism and autophagy. Recent studies have revealed that one ancestral function of AMPK is to promote mitochondrial health, and multiple newly discovered targets of AMPK are involved in various aspects of mitochondrial homeostasis, including mitophagy This Review discusses how AMPK functions as a central mediator of the cellular response to energetic stress and mitochondrial insults and coordinates multiple features of autophagy and mitochondrial biology.

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Section: Ampk Regulates Autophagy and Mitophagymentioning

confidence: 99%

AMPK: guardian of metabolism and mitochondrial homeostasis

Herzig

Shaw

2017

Nat Rev Mol Cell Biol

2,750

2,008

View full text Add to dashboard Cite

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“…ACSS2 is essential for protein acetylation by producing acetyl CoA, which has an important role in many biological processes. ACSS2 can increase histone H3 acetylation in specific regions, which is vital to autophagy, cell survival and tumourigenesis [28,29]. In particular, previous studies have shown that ACSS2 can promote brain carcinogenesis by increasing the expression of autophagy-related factors, such as LAMP1.…”

Section: Cellular Physiology and Biochemistry Cellular Physiology Andmentioning

confidence: 99%

Acetyl-CoA Synthetase 2 Promotes Cell Migration and Invasion of Renal Cell Carcinoma by Upregulating Lysosomal-Associated Membrane Protein 1 Expression

Guo

Gui

2018

Cell Physiol Biochem

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Background/Aims: Reprogramming energy metabolism is an emerging hallmark of many cancers, and this alteration is especially evident in renal cell carcinomas (RCCs). However, few studies have been conducted on lipid metabolism. This study investigated the function and mechanism of lipid metabolism-related acetyl-CoA synthetase 2 (ACSS2) in RCC development, cell migration and invasion. Methods: Quantitative real-time PCR (qRT-PCR) was used to determine the expression of ACSS2 in cancer tissue and adjacent tissue. The inhibition of ACSS2 expression was achieved by RNA interference, which was confirmed by qRT-PCR and Western blotting. Cell proliferation and apoptosis were detected by a CCK8 assay and a flow cytometry analysis, respectively. Cell migration and invasion were determined by the scratch and transwell assays. Following the knockdown of ACSS2 expression, the expression of the autophagy-related factor LAMP1 was measured by qRT-PCR and Western blotting. Results: Compared to adjacent tissues, ACSS2 expression was upregulated in RCC cancer tissues and positively correlated with metastasis. Inhibition of ACSS2 had no effect on RCC cell proliferation or apoptosis. However, decreased ACSS2 expression was found to inhibit RCC cell migration and invasion. ACSS2 was determined to promote the expression of LAMP1, which can also promote cell migration. This pathway may be considered a potential mechanism through which ACSS2 participates in RCC development. Conclusion: These data suggest that ACSS2 is an important factor for promoting RCC development and is essential for cell migration and invasion, which it promotes by increasing the expression of LAMP1. Taken together, these findings reveal a potential target for the diagnosis and treatment of RCC.

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“…It would be interesting to determine if AMPK-mediated activation of TFEB regulates the catalytic activity of calcineurin or interaction between TFEB and calcineurin. It has also been shown that nutrient/glucose deprivation-induced AMPK activation regulates lysosomal and autophagy gene expression through phosphorylation at S659 and nuclear localization of ACSS2 (75). Phosphorylated ACSS2 forms a complex with TFEB, which modulates lysosomal and autophagosomal genes by locally producing acetyl-CoA for histone [ 3 H] acetylation in the promoter regions of these genes.…”

Section: Discussionmentioning

confidence: 99%

AMPK promotes induction of the tumor suppressor FLCN through activation of TFEB independently of mTOR

et al. 2019

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AMPK is a central regulator of energy homeostasis. AMPK not only elicits acute metabolic responses but also promotes metabolic reprogramming and adaptations in the long‐term through regulation of specific transcription factors and coactivators. We performed a whole‐genome transcriptome profiling in wild‐type (WT) and AMPK‐deficient mouse embryonic fibroblasts (MEFs) and primary hepatocytes that had been treated with 2 distinct classes of small‐molecule AMPK activators. We identified unique compound‐dependent gene expression signatures and several AMPK‐regulated genes, including folliculin (Flcn), which encodes the tumor suppressor FLCN. Bioinformatics analysis highlighted the lysosomal pathway and the associated transcription factor EB (TFEB) as a key transcriptional mediator responsible for AMPK responses. AMPK‐induced Flcn expression was abolished in MEFs lacking TFEB and transcription factor E3, 2 transcription factors with partially redundant function; additionally, the promoter activity of Flcn was profoundly reduced when its putative TFEB‐binding site was mutated. The AMPK‐TFEB‐FLCN axis is conserved across species; swimming exercise in WT zebrafish induced Flcn expression in muscle, which was significantly reduced in AMPK‐deficient zebrafish. Mechanistically, we have found that AMPK promotes dephosphorylation and nuclear localization of TFEB independently of mammalian target of rapamycin activity. Collectively, we identified the novel AMPK‐TFEB‐FLCN axis, which may function as a key cascade for cellular and metabolic adaptations.—Collodet, C., Foretz, M., Deak, M., Bultot, L., Metairon, S., Viollet, B., Lefebvre, G., Raymond, F., Parisi, A., Civiletto, G., Gut, P., Descombes, P., Sakamoto, K. AMPK promotes induction of the tumor suppressor FLCN through activation of TFEB independently of mTOR. FASEB J. 33, 12374–12391 (2019). http://www.fasebj.org

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Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy

Cited by 268 publications

References 54 publications

AMPK: guardian of metabolism and mitochondrial homeostasis

AMPK: guardian of metabolism and mitochondrial homeostasis

Acetyl-CoA Synthetase 2 Promotes Cell Migration and Invasion of Renal Cell Carcinoma by Upregulating Lysosomal-Associated Membrane Protein 1 Expression

AMPK promotes induction of the tumor suppressor FLCN through activation of TFEB independently of mTOR

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