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.

The UPR preserves mature oligodendrocyte viability and function in adults by regulating autophagy of PLP

“…Statistical analyses were done with a 1-way ANOVA with Tukey's posttest; *P < 0.05. double-KO mice compared with WT mice, PERK-KO mice, and ATF6α-KO mice at P28, and in the optic nerve of double-KO mice compared with WT mice and PERK-KO mice at P45, but were not decreased at P21. Both SEZ6L2 and GNPTAB participate in the transport of the lysosomal hydrolase cathepsin D from the trans-Golgi network to the lysosome (40)(41)(42)(43). We further assessed the subcellular localization of cathepsin D in oligodendrocytes of these mice.…”

SEZ6L2 knockdown impairs tumour growth by promoting caspase‐dependent apoptosis in colorectal cancer

“…Until now, the function of SEZ6L2 was poorly understood; however, studies have begun to reveal some of its basic functions. A previous study by Boonen et al suggested that SEZ6L2 is involved in the trafficking of cathepsin D to endosomes, and hence modulates neurite outgrowth. SiRNA‐mediated down‐regulation of SEZ6L2 prevents phosphorylation of adducin and neuritogenesis .…”

“…It has been reported that mice deficient in SEZ6L2 suffer from motor ataxia, impaired cognition and abnormal neuronal innervation (a disturbance of the cerebellar synaptic maturation in mutant mice lacking BSRPs, a novel brain‐specific receptor‐like protein family) . Cleavage of SEZ6L2, which is mediated by cathepsin D, induces neurite outgrowth . In one patient suffering from cerebellar ataxia and retinopathy, anti‐SEZ6L2 antibodies were detected, which were also associated with progressive cerebellar ataxia .…”

Correlative light and electron microscopy reveals discrepancy between gold and fluorescence labelling

“…The morphology of subcellular structures wherein they reside remains invisible. Conversely, electron microscopy (EM) enables observations at nanometre‐scale resolution and is therefore often employed to gain ultrastructural characterization of the subcellular environment pertinent to the biomolecules initially investigated with FM (Predescu et al ., ; Robenek et al ., ; Sarnataro et al ., ; Choi et al ., ; Boonen et al ., ).…”

“…Tel: +31-71-5269294; e-mail: a.j.koster@lumc.nl olution and is therefore often employed to gain ultrastructural characterization of the subcellular environment pertinent to the biomolecules initially investigated with FM (Predescu et al, 2003;Robenek et al, 2006;Sarnataro et al, 2009;Choi et al, 2015;Boonen et al, 2016).…”