The transport of soluble lysosomal hydrolases from the Golgi complex to lysosomes

Based on proteomic analyses the lysosome contains over 50 soluble lysosomal hydrolases plus several accessory integral membrane proteins (Journet et al. 2002; Sleat et al. 2005; Kolman et al. 2005; Czupalla et al. 2006). These proteins are synthesized at the rough endoplasmic reticulum and travel along the secretory pathway till they reach the trans-Golgi network (TGN) where they are sorted and delivered to pre-lysosomal compartments. Mannose-6-Phosphate (M6P) isthe sorting signal for the majority, though not all, of the proteins destined to lysosomes. M6P groups have, in fact, been found also in proteins with no obvious lysosomal localization (Sleat et al. 2006). On the other hand, proteins not bearing the M6P group can also be targeted to the lysosome and proteins bearing the M6P group can be delivered to the lysosome independently of this group (MPR-independent transport). Particularly intriguing is the finding of the M6P group on secreted polypeptides such as the hydrolase plasma a-fucosidase or the hormone precursor Vasopressin-Neurophysisn 2 Copeptin and on endoplasmic reticulum (ER)-resident proteins such as the chaperone Microsomal Stress 70 Protein ATPase or the Sulfatase-modifying Factor 2 Precursor (Sleat et al. 2006). The functional significance of M6P in non-lysosomal resident protein remains at present a conundrum. Whatever the significance, this means that the presence of M6P does not impose the ineluctable targeting of a protein toward the endosomal compartment and, at one time, it reveals that generation of M6P occurs at a site relatively distant from where the MPRs bind their ligands and that other receptors specific for peptide signal may rescue these proteins before they encounter the MPRs.