ACSS2-related autophagy has a dual impact on memory

Autophagy is an intracellular degenerative pathway which is responsible for neuronal survival. Under the condition of nutrient deprivation, autophagy can lead to dysfunction in memory consolidation. AMPK/mTOR pathway is currently the most studied autophagy mechanism, while recently researchers have proved ACSS2 can also affect autophagy. ACSS2 is phosphorylated at Ser659 by AMPK and then forms a translocation complex with Importin α5 to translocate into the nucleus. This process interacts with TFEB, resulting in upregulated expression of lysosomal and autophagosomal genes. These upregulations inhibit synaptic plasticity and hence memory functions. On the other hand, ACSS2 is also recognized as a regulator of histone acetylation. After recruiting CBP/p300 and activating CBP's HAT activity in the nucleus, ACSS2 maintains the level of localized histone acetylation by recapturing acetate from histone deacetylation to reform acetyl-CoA, providing substrates for HAT. The increase of histone acetylation locally enhanced immediate early gene transcription, including Egr2, Fos, Nr2f2, Sgk1, and Arc, to benefit neuronal plasticity and memory in many ways.