Molecular Cell
Volume 66, Issue 5, 1 June 2017, Pages 684-697.e9
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Article
Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy

https://doi.org/10.1016/j.molcel.2017.04.026Get rights and content
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Highlights

  • ACSS2 phosphorylation at S659 by AMPK induces nuclear translocation of ACSS2

  • TFEB-associated ACSS2 binds to lysosomal and autophagy gene promoter regions

  • Nuclear ACSS2 locally generates acetyl-CoA for H3 acetylation and gene expression

  • Nuclear ACSS2 promotes lysosomal biogenesis, autophagy, and brain tumorigenesis

Summary

Overcoming metabolic stress is a critical step in tumor growth. Acetyl coenzyme A (acetyl-CoA) generated from glucose and acetate uptake is important for histone acetylation and gene expression. However, how acetyl-CoA is produced under nutritional stress is unclear. We demonstrate here that glucose deprivation results in AMP-activated protein kinase (AMPK)-mediated acetyl-CoA synthetase 2 (ACSS2) phosphorylation at S659, which exposed the nuclear localization signal of ACSS2 for importin α5 binding and nuclear translocation. In the nucleus, ACSS2 binds to transcription factor EB and translocates to lysosomal and autophagy gene promoter regions, where ACSS2 incorporates acetate generated from histone acetylation turnover to locally produce acetyl-CoA for histone H3 acetylation in these regions and promote lysosomal biogenesis, autophagy, cell survival, and brain tumorigenesis. In addition, ACSS2 S659 phosphorylation positively correlates with AMPK activity in glioma specimens and grades of glioma malignancy. These results underscore the significance of nuclear ACSS2-mediated histone acetylation in maintaining cell homeostasis and tumor development.

Keywords

ACSS2
nucleus
acetyl-CoA
TFEB
AMPK
lysosomal biogenesis
autophagy
tumor development

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