Rabex-5 Protein Regulates the Endocytic Trafficking Pathway of Ubiquitinated Neural Cell Adhesion Molecule L1 |
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Authors: | Yoshikatsu Aikawa |
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Affiliation: | From the Laboratory of Neural Membrane Biology, Graduate School of Brain Science, Doshisha University, 1-3 Miyakodani, Kyotanabe, Kyoto 610-0394, Japan |
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Abstract: | Ubiquitination of integral membrane proteins is a common posttranslational modification used to mediate endocytosis and endocytic sorting of cell surface proteins in eukaryotic cells. Ubiquitin (Ub)-binding proteins (UBPs) regulate the stability, function, and localization of ubiquitinated cell surface proteins in the endocytic pathway. Here, I report that the immunoglobulin superfamily cell adhesion molecule L1 undergoes ubiquitination and dephosphorylation on the plasma membrane upon L1 antibody-induced clustering, which mimics L1-L1 homophilic binding, and that these modifications are critical for obtaining the maximal rate of internalization and trafficking to the lysosome, but not to the proteasome. Notably, L1 antibody-induced clustering leads to the association of ubiquitinated L1 with Rabex-5, a UBP and guanine nucleotide exchange factor for Rab5, via interaction with the motif interacting with Ub (MIU) domain, but not the A20-type zinc finger domain. This interaction specifically depends on the presence of an Ub moiety on lysine residues in L1. Rabex-5 expression accelerates the internalization rates of L1WT and L1Y1176A, a tyrosine-based motif mutant, but not L1K11R, an ubiquitination-deficient mutant, leading to the accumulation of ubiquitinated L1 on endosomes. In contrast, RNA interference-mediated knockdown of Rabex-5 impairs the internalizations of L1WT and L1Y1176A, but not L1K11R from the plasma membrane. Overall, these results provide a novel mechanistic insight into how Rabex-5 regulates internalization and postendocytic trafficking of ubiquitinated L1 destined for lysosomal degradation. |
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Keywords: | Cell Adhesion Endocytosis Guanine Nucleotide Exchange Factor (GEF) Membrane Trafficking Rab Guanine Nucleotide Exchange Factor for Rab5 Neural Cell Adhesion Molecule L1 (L1cam) Ubiquitin-binding Domains |
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