Abstract / Summary
Despite extensive characterization of cytosolic and nuclear acetylation, the functional relevance of luminal ER-Nε-lysine acetylation in the nervous system remains poorly understood. This modification is mediated by a coordinated metabolic–secretory axis involving acetyl-CoA availability and the ER-resident acetyltransferases ATase-1 (NAT8B) and ATase-2 (NAT8), which depend on acetyl-CoA import into the ER via the transporter SLC33A1 (AT-1). Upstream, the citrate transporters SLC25A1 and SLC13A5 contribute to shaping the cytosolic acetyl-CoA pool. Emerging evidence identifies this pathway as a key regulator of proteostasis within the early secretory pathway, linking cellular metabolism to protein processing, trafficking, and degradation. Recent studies in neurological disease models suggest that excessive activation of this machinery may exert pathogenic effects through distinct mechanisms. In experimental models of autism spectrum disorder (ASD), increased ER acetylation is associated with altered secretory pathway flux, impaired synaptic proteostasis, and abnormal neuronal connectivity, ultimately leading to ASD-like phenotypes. In Alzheimer’s disease (AD) models, excessive ER-Nε-lysine acetylation appears to suppress reticulophagic clearance of aggregation-prone proteins within the secretory pathway, whereas genetic or pharmacological reduction of AT-1/ATase activity enhances proteostatic clearance and confers protective effects. In this opinion article, we discuss ER-Nε-lysine acetylation as a context-dependent regulator of proteostasis in neurodevelopmental and neurodegenerative disease models. We highlight key unresolved questions regarding acetylation substrates, relevance to human biology, and future therapeutic opportunities. We further consider its potential relevance to additional disorders, including multiple sclerosis, where its contribution remains largely unexplored.