title: Cathepsin E generates a sumoylated intracellular fragment of the cell adhesion molecule L1 to promote neuronal and Schwann cell migration as well as myelination.
abstract: The cell adhesion molecule L1 regulates cellular responses in the developing and adult nervous system. Here, we show that stimulation of cultured mouse cerebellar neurons by a function-triggering L1 antibody leads to cathepsin E-mediated generation of a sumoylated 30 kDa L1 fragment (L1-30) and to import of L1-30 into the nucleus. Mutation of the sumoylation site at K1172 or the cathepsin E cleavage site at E1167 abolishes generation of L1-30, while mutation of the nuclear localization signal at K1147 prevents nuclear import of L1-30. Moreover, the aspartyl protease inhibitor pepstatin impairs the generation of L1-30 and inhibits L1-induced migration of cerebellar neurons and Schwann cells as well as L1-dependent in vitro myelination on axons of dorsal root ganglion neurons by Schwann cells. L1-stimulated migration of HEK293 cells expressing L1 with mutated cathepsin E cleavage site is diminished in comparison to migration of cells expressing non-mutated L1. In addition, L1-stimulated migration of HEK293 cells expressing non-mutated L1 is also abolished upon knock-down of cathepsin E expression and enhanced by over-expression of cathepsin E. The findings of the present study indicate that generation and nuclear import of L1-30 regulate neuronal and Schwann cell migration as well as myelination. Cell adhesion molecule L1 regulates cellular responses in the developing and adult nervous system. L1 stimulation triggers sumoylation and cleavage of L1, thus generating the L1-70 fragment (1) which is cleaved by cathepsin E (2) yielding the L1-30 fragment that is imported to the nucleus (3), may bind to DNA and/or nuclear proteins (4), to regulate diverse cellular functions.
authors.affiliation: Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Lutz
authors.forename: Gerrit
authors.initials: G
authors.lastname: Wolters-Eisfeld
authors.forename: Melitta
authors.initials: M
authors.lastname: Schachner
authors.forename: Ralf
authors.initials: R
authors.lastname: Kleene
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology; D020059:Cathepsin E / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology*; D002531:Cerebellum / Q000166:cytology; D018920:Coculture Techniques; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000502:physiology; D009186:Myelin Sheath / Q000502:physiology*; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D016501:Neurites / Q000187:drug effects; D009474:Neurons / Q000502:physiology*; D010436:Pepstatins / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D012583:Schwann Cells / Q000502:physiology*; D058207:Sumoylation / Q000235:genetics / Q000502:physiology*
chemical_list: D039842:Neural Cell Adhesion Molecule L1; D010436:Pepstatins; D010446:Peptide Fragments; D011480:Protease Inhibitors; D034741:RNA, Small Interfering; D020059:Cathepsin E; C031375:pepstatin
keywords: cathepsin; cell adhesion molecule L1; myelination; neuronal migration; nuclear import; sumoylation