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How, in the absence of a functional mannose 6-phosphate (Man-6-P) signal-dependent transport pathway, some acid hydrolases remain sorted to endosomes/lysosomes in the brain is poorly understood. We demonstrate that cathepsin D binds to mouse Sez6l2, a type 1 transmembrane protein predominantly expressed in 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 knock-down of GlcNAc-1-phosphotransferase in HeLa cells (i.e. unable to synthesize Man-6-P signals). Interestingly, cleavage of Sez6l2 by cathepsin D generates a N-terminal soluble fragment that induces neurite outgrowth, while 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.

Cathepsin D and its newly identified transport receptor Sez6l2 can modulate neurite outgrowth