Cell adhesion molecule L1 regulates multiple cell functions, and L1 deficiency is linked to several neural diseases. Recently, we have identified methyl CpG binding protein 2 (MeCP2) as a potential binding partner of the intracellular L1 domain. By ELISA we show here that L1’s intracellular domain binds directly to MeCP2 via the sequence motif KDET. Proximity ligation assay with cultured cerebellar and cortical neurons suggests a close association between L1 and MeCP2 in nuclei of neurons. Immunoprecipitation using MeCP2 antibodies and nuclear mouse brain extracts indicates that MeCP2 interacts with an L1 fragment of ~55 kDa (L1−55). Proximity ligation assay indicates that metalloproteases, β-site of amyloid precursor protein cleaving enzyme (BACE1) and ɣ-secretase, are involved in the generation of L1−55. Reduction in MeCP2 expression by siRNA decreases L1-dependent neurite outgrowth from cultured cortical neurons as well as the migration of L1-expressing HEK293 cells. Moreover, L1 siRNA, MeCP2 siRNA, or a cell-penetrating KDET-containing L1 peptide leads to reduced levels of myocyte enhancer factor 2C (Mef2c) mRNA and protein in cortical neurons, suggesting that the MeCP2/L1 interaction regulates Mef2c expression. Altogether, the present findings indicate that the interaction of the novel fragment L1−55 with MeCP2 affects L1-dependent functions, such as neurite outgrowth and neuronal migration.

The modulation of neurotransmitter receptor density is an important molecular mechanism underlying synaptic plasticity. Acid-sensing ion channel 1a (ASIC1a), a receptor for protons, plays an important role in synaptic transmission. In this study, we used high-resolution proteomic analysis to identify prenylcysteine oxidase 1 like (PCYOX1L) as a hitherto unknown interaction partner of ASIC1a. We found that PCYOX1L is a secreted protein that promotes ASIC1a assembly. PCYOX1L was indispensable for ASIC1a expression in the plasma membrane and synaptosomes, and the genetic deletion of PCYOX1L severely impaired hippocampal long-term potentiation. Endocytosed PCYOX1L promoted plasma membrane expression of ASIC1a, and PCYOX1L secreted from astrocytes induced ASIC1a activity in neurons. Our findings reveal that a secreted protein, PCYOX1L, is a checkpoint for the plasma membrane expression of a synaptic ion channel.