Naa10 regulates hippocampal neurite outgrowth via Btbd3 N-α-acetylation-mediated actin dynamics

Abstract

Protein N--acetylation is widespread in eukaryotes, yet its neuronal role remains unclear. Mutations in human N--acetyltransferase 10 (NAA10) lead to developmental defects affecting brain function, such as intellectual disability and autism. We found that hippocampal CA1-specific Naa10-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 through Naa10 knockout or by expressing an N--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 the Naa10 knockout-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 human NAA10 mutations. 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--acetylation and neuronal function, providing insight into the mechanism underlying brain disorders associated with human NAA10 mutations. HIGHLIGHTSO_LIHippocampal CA1-specific Naa10 KO leads to anxiety C_LIO_LIHippocampal CA1-specific Naa10 KO reduces hippocampal dendritic complexity C_LIO_LINaa10 promotes neurite outgrowth by N-acetylating Btbd3 C_LIO_LINaa10-mediated Btbd3 N--acetylation promotes CapZb binding to F-actin C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/583166v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@180da41org.highwire.dtl.DTLVardef@7921c6org.highwire.dtl.DTLVardef@9859b0org.highwire.dtl.DTLVardef@28687c_HPS_FORMAT_FIGEXP M_FIG C_FIG