CaMKII-LUZP1 signaling couples cytoskeletal acetylation and autophagy to drive neuronal plasticity

Abstract

Cytoskeletal acetylation and autophagy are fundamental drivers of neuronal plasticity, yet how these pathways are coordinated across subcellular compartments remains unknown. Here, we identify LUZP1 as a signaling organizer that couples cytoskeletal acetylation to autophagy in hippocampal neurons. LUZP1 deficiency impaired neurite outgrowth and dendritic spine maturation while promoting ciliary elongation; these phenotypes were partially mirrored in neuron-specific Luzp1 knockout mice, which also showed altered locomotor behavior. Mechanistically, LUZP1 promoted neurite extension by enhancing ATAT1-dependent -tubulin acetylation while driving spine maturation and limiting ciliary growth by restraining HDAC6-dependent cortactin (CTTN) deacetylation. An acetylation-mimetic CTTN mutant rescued both spine and ciliary defects caused by LUZP1 deficiency. In parallel, blocking autophagy-dependent OFD1 degradation attenuated ciliary elongation, linking CTTN deacetylation to increased autophagy under LUZP1-deficient conditions. Finally, activated CaMKII associated with LUZP1 and selectively enhanced its interaction with HDAC6 and CTTN, coupling neuronal activity to cytoskeletal remodeling. Together, these findings identify a CaMKII-LUZP1 pathway that integrates cytoskeletal acetylation with autophagy to coordinate neuronal morphogenesis and ciliary homeostasis. HighlightsO_LILUZP1 couples cytoskeletal acetylation to autophagy in hippocampal neurons C_LIO_LILUZP1 promotes neurite extension through ATAT1-dependent -tubulin acetylation C_LIO_LILUZP1 restrains HDAC6-CTTN signaling to drive spine maturation and limit ciliary growth C_LIO_LICaMKII selectively strengthens the LUZP1-HDAC6-CTTN pathway C_LI