Interaction of L1CAM with LC3 Is Required for L1-Dependent Neurite Outgrowth and Neuronal Survival

Abstract

The neural cell adhesion molecule L1 (also called L1CAM or CD171) functions not only in cell migration, but also in cell survival, differentiation, myelination, neurite outgrowth, and signaling during nervous system development and in adults. The proteolytic cleavage of L1 in its extracellular domain generates soluble fragments which are shed into the extracellular space and transmembrane fragments that are internalized into the cell and transported to various organelles to regulate cellular functions. To identify novel intracellular interaction partners of L1, we searched for protein–protein interaction motifs and found two potential microtubule-associated protein 1 light-chain 3 (LC3)-interacting region (LIR) motifs within L1, one in its extracellular domain and one in its intracellular domain. By ELISA, immunoprecipitation, and proximity ligation assay using L1 mutant mice lacking the 70 kDa L1 fragment (L1-70), we showed that L1-70 interacts with LC3 via the extracellular LIR motif in the fourth fibronectin type III domain, but not by the motif in the intracellular domain. The disruption of the L1-LC3 interaction reduces L1-mediated neurite outgrowth and neuronal survival.

Mice Mutated in the First Fibronectin Domain of Adhesion Molecule L1 Show Brain Malformations and Behavioral Abnormalities

“…Since interactions of L1 with methyl CpG binding protein 2, estrogen receptor and retinoid X receptor were similar in wild-type and L1/687 neurons [27,33], we can assume that certain heterophilic interaction partners can interact with full-length L1 carrying the R/A687 mutation or with L1 fragments generated in L1/687 mice. In contrast, other heterophilic interactions depend on L1-70, like the interaction of L1 with microtubule-associated protein 1A/1B-light chain 3, and these are disturbed in L1/687 mice [55] and can contribute to the mutant phenotype. Our findings help to explain how mutations in L1 differently alter brain development and functioning, leading to moderate to severe L1 syndrome phenotypes, suggesting that enhancing mitochondrial and neuronal functions in L1 syndrome patients could help to ameliorate L1 syndrome.…”

“…Furthermore, we showed that L1-70 interacts with microtubuleassociated protein 1A/1B-light chain 3, topoisomerase I, peroxisome proliferator-activated receptor γ and β-nicotinamide adenine dinucleotide hydrate dehydrogenase (ubiquinone) flavoprotein 2, and, in L1/687 cells, these interactions did not take place. In contrast, the retinoid X receptor, estrogen receptor α, splicing factor proline/glutamine-rich, non-POU domain-containing octamer-binding protein and paraspeckle component 1 interacted with L1 with R687V mutation and did not bind to L1-70 [27,55]. We analyzed in vivo the influence of the R to A substitution at position 687 of L1 on brain development and nervous system functions in adult mice.…”

Synaptic cell adhesion molecules contribute to the pathogenesis and progression of fragile X syndrome

“…L1-CAM is expressed in the central nervous system by subpopulations of neurons and on glial cells in the peripheral nervous system ( Rathjen and Schachner, 1984 ; Seilheimer and Schachner, 1987 ). L1-CAM is involved in adhesion between neurons, the formation of neural fiber bundles, and the growth of nerve processes ( Moos et al, 1988 ; Wang et al, 2012 ; Congiu et al, 2022 ; Loers et al, 2023 ). It mediates homophilic and heterophilic interactions between neurons ( Kadmon et al, 1990a ; Sytnyk et al, 2017 ; Stoyanova and Lutz, 2022 ) and cooperates with NCAM through a mechanism termed assisted homophilic adhesion ( Kadmon et al, 1990b ).…”

“…According to the findings of Loers et al (2023) , L1 siRNA has an inhibitory effect on the expression of long-chain autism genes neurexin 1 ( NRXN1 ) and neuroligin 1 ( NLGN1 ) and mitochondrial-encoding genes such as NADH ubiquinone oxidoreductase core subunit 2 ( ND2 ). Additionally, Lai et al (2016) found that FMRP binds to NLGN1 and NLGN3 mRNA, whereas Dahlhaus and El-Husseini (2010) revealed an association between the core symptoms of FXS and the neurexin-neuroligin network.…”