Naa10 regulates hippocampal neurite outgrowthviaBtbd3 N-α-acetylation-mediated actin dynamics

Abstract

AbstractProtein N-α-acetylation is widespread in eukaryotes, yet its neuronal role remains unclear. Mutations in human N-α-acetyltransferase 10 (NAA10) lead to developmental defects affecting brain function, such as intellectual disability and autism. We found that hippocampal CA1-specificNaa10-knockout mice exhibit anxiety and reduced hippocampal dendritic complexity. Mechanistically, Naa10 promotes neurite outgrowth by acetylating BTB/POZ domain-containing protein 3 (Btbd3), crucial for the interaction of Btbd3 with filamentous actin (F-actin)-capping protein subunit beta (CapZb). Disrupting the Btbd3/CapZb interaction, either throughNaa10knockout or by expressing an N-α-acetylation-defective Btbd3 mutant, diminishes CapZb binding to F-actin and reduces neurite outgrowth. Moreover, cytochalasin D, a compound like CapZb in capping the barbed end of F-actin, rescues theNaa10knockout-induced neurite reduction in hippocampal primary neurons. These findings unveil the role of Naa10 in enhancing hippocampal neurite outgrowth through the Btbd3-CapZb-F-actin axis, shedding light on potential mechanisms underlying X-linked Ogden syndrome resulting from humanNAA10mutations.eTOCChou et al. demonstrate that Naa10 promotes neurite outgrowth by N-acetylating Btbd3, facilitating the binding of the filamentous actin capping protein subunit beta (CapZb) to F-actin. Their study establishes a connection between protein N-α-acetylation and neuronal function, providing insight into the mechanism underlying brain disorders associated with human NAA10 mutations.HIGHLIGHTSHippocampal CA1-specificNaa10KO leads to anxietyHippocampal CA1-specificNaa10KO reduces hippocampal dendritic complexityNaa10 promotes neurite outgrowth by N-acetylating Btbd3Naa10-mediated Btbd3 N-α-acetylation promotes CapZb binding to F-actinGraphical Abstract