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

• Published in: Molecular cell Vol. 66; no. 5; pp. 684 - 697.e9
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2017
• Subjects: Acetate-CoA Ligase - genetics; Acetate-CoA Ligase - metabolism; Acetyl Coenzyme A - metabolism; acetyl-CoA; Acetylation; ACSS2; Active Transport, Cell Nucleus; alpha Karyopherins - genetics; alpha Karyopherins - metabolism; AMP-Activated Protein Kinases - metabolism; AMPK; Animals; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism; Binding Sites; Brain Neoplasms - enzymology; Brain Neoplasms - genetics; Brain Neoplasms - pathology; Cell Line, Tumor; Cell Nucleus - enzymology; Cell Nucleus - pathology; Cell Survival; Energy Metabolism; Gene Expression Regulation, Neoplastic; Glioblastoma - enzymology; Glioblastoma - genetics; Glioblastoma - pathology; Histones - metabolism; Humans; lysosomal biogenesis; Lysosomes - metabolism; Male; Mice, Inbred BALB C; Mice, Nude; nucleus; Organelle Biogenesis; Phosphorylation; Promoter Regions, Genetic; Protein Binding; Protein Processing, Post-Translational; RNA Interference; Stress, Physiological; TFEB; Transcription, Genetic; Transfection; tumor development; ACSS2; lysosomal biogenesis; autophagy; TFEB; nucleus; AMPK; acetyl-CoA; tumor development
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2017.04.026

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. [Display omitted] •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 Nutritional stresses, which restrict acetyl-CoA production from glucose or acetate uptake, result in AMPK-mediated phosphorylation and nuclear translocation of ACSS2. ACSS2 binds to TFEB, translocates to lysosomal and autophagosomal gene promoter regions, and incorporates acetate from histone acetylation turnover to locally produce acetyl-CoA for histone H3 acetylation and gene expression.