title: Cathepsin D and its newly identified transport receptor SEZ6L2 can modulate neurite outgrowth.
abstract: How, in the absence of a functional mannose 6-phosphate (Man-6-P)-signal-dependent transport pathway, some acid hydrolases remain sorted to endolysosomes in the brain is poorly understood. We demonstrate that cathepsin D binds to mouse SEZ6L2, a type 1 transmembrane protein predominantly expressed in the brain. Studies of the subcellular trafficking of SEZ6L2, and its silencing in a mouse neuroblastoma cell line reveal that SEZ6L2 is involved in the trafficking of cathepsin D to endosomes. Moreover, SEZ6L2 can partially correct the cathepsin D hypersecretion resulting from the knockdown of UDP-GlcNAc:lysosomal enzyme GlcNAc-1-phosphotransferase in HeLa cells (i.e. in cells that are unable to synthesize Man-6-P signals). Interestingly, cleavage of SEZ6L2 by cathepsin D generates an N-terminal soluble fragment that induces neurite outgrowth, whereas its membrane counterpart prevents this. Taken together, our findings highlight that SEZ6L2 can serve as receptor to mediate the sorting of cathepsin D to endosomes, and suggest that proteolytic cleavage of SEZ6L2 by cathepsin D modulates neuronal differentiation.
authors.affiliation: URPhyM-Laboratoire de Chimie Physiologique, University of Namur, 61 rue de Bruxelles, Namur 5000, Belgium.
authors.forename: Marielle
authors.initials: M
authors.lastname: Boonen
authors.affiliation: URPhyM-Laboratoire de Chimie Physiologique, University of Namur, 61 rue de Bruxelles, Namur 5000, Belgium.
authors.forename: Catherine
authors.initials: C
authors.lastname: Staudt
authors.affiliation: URPhyM-Laboratoire de Chimie Physiologique, University of Namur, 61 rue de Bruxelles, Namur 5000, Belgium.
authors.forename: Florentine
authors.initials: F
authors.lastname: Gilis
authors.affiliation: Department of Cell Biology, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3584 CX, The Netherlands.
authors.forename: Viola
authors.initials: V
authors.lastname: Oorschot
authors.affiliation: Department of Cell Biology, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3584 CX, The Netherlands.
authors.forename: Judith
authors.initials: J
authors.lastname: Klumperman
authors.affiliation: URPhyM-Laboratoire de Chimie Physiologique, University of Namur, 61 rue de Bruxelles, Namur 5000, Belgium michel.jadot@unamur.be.
authors.forename: Michel
authors.initials: M
authors.lastname: Jadot
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism; D002402:Cathepsin D / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D011992:Endosomes / Q000378:metabolism / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016501:Neurites / Q000378:metabolism* / Q000502:physiology; D009447:Neuroblastoma / Q000378:metabolism / Q000503:physiopathology; D021381:Protein Transport / Q000502:physiology; D017855:Transferases (Other Substituted Phosphate Groups) / Q000378:metabolism; D014530:Uridine Diphosphate / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; C513545:SEZ6L2 protein, human; D014530:Uridine Diphosphate; D017855:Transferases (Other Substituted Phosphate Groups); C505859:alpha-beta GlcNAc-1-phosphotransferase, human; D002402:Cathepsin D
keywords: Lysosomal hydrolase; Mannose 6-phosphate-independent; Transport receptor