Catalyzes the synthesis of acetyl-CoA from short-chain fatty acids ( ). Acetate is the preferred substrate (, ). Can also utilize propionate with a much lower affinity (By similarity). Nuclear ACSS2 promotes glucose deprivation-induced lysosomal biogenesis and autophagy, tumor cell survival and brain tumorigenesis . Glucose deprivation results in AMPK-mediated phosphorylation of ACSS2 leading to its translocation to the nucleus where it binds to TFEB and locally produces acetyl-CoA for histone acetylation in the promoter regions of TFEB target genes thereby activating their transcription . The regulation of genes associated with autophagy and lysosomal activity through ACSS2 is important for brain tumorigenesis and tumor survival . Acts as a chromatin-bound transcriptional coactivator that up-regulates histone acetylation and expression of neuronal genes (By similarity). Can be recruited to the loci of memory-related neuronal genes to maintain a local acetyl-CoA pool, providing the substrate for histone acetylation and promoting the expression of specific genes, which is essential for maintaining long-term spatial memory (By similarity).
Subcellular locations: Cytoplasm, Cytosol, Cytoplasm, Nucleus
Glucose deprivation results in its AMPK-dependent phosphorylation and subsequent nuclear translocation . Phosphorylation at Ser-659, leads to exposure of its nuclear localization signal which is required for its interaction with KPNA1 and subsequent translocation to the nucleus . Found in the cytoplasm in undifferentiated neurons and upon differentiation, translocates to nucleus (By similarity).