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Lrp1/LDL receptor play critical roles in mannose 6-phosphate-independent lysosomal enzyme targeting

Item Type:Article
Title:Lrp1/LDL receptor play critical roles in mannose 6-phosphate-independent lysosomal enzyme targeting
Creators Name:Markmann, S. and Thelen, M. and Cornils, K. and Schweizer, M. and Brocke-Ahmadinejad, N. and Willnow, T. and Heeren, J. and Gieselmann, V. and Braulke, T. and Kollmann, K.
Abstract:Most lysosomal enzymes require mannose 6-phosphate (M6P) residues for efficient receptor-mediated lysosomal targeting. Although the lack of M6P residues results in missorting and hypersecretion, selected lysosomal enzymes reach normal levels in lysosomes of various cell types suggesting the existence of M6P-independent transport routes. Here, we quantify the lysosomal proteome in M6P-deficient mouse fibroblasts (PT(ki) ) using Stable Isotope Labeling by Amino acids in Cell culture (SILAC)-based comparative mass spectrometry, and find unchanged amounts of 20 % of lysosomal enzymes, including cathepsin D and B (Ctsd, Ctsb). Examination of fibroblasts from a new mouse line lacking both M6P and sortilin, a candidate for M6P-independent transport of lysosomal enzymes, revealed that sortilin does not act as cargo receptor for Ctsb and Ctsd. Using fibroblast lines deficient for endocytic lipoprotein receptors we could demonstrate that both LDL receptor and Lrp1 mediate the internalization of non-phosphorylated Ctsb and Ctsd. Furthermore, the presence of Lrp1 inhibitor increased the secretion of Ctsd from PT(ki) cells. These findings establish Lrp1 and LDL receptors in M6P-independent secretion-recapture targeting mechanism for lysosomal enzymes.
Keywords:Low Density Lipoprotein-Related Receptor, Lysosomal Storage Disorder, Lysosomal Targeting, Mannose 6-Phosphate, Receptor-Mediated Endocytosis, Sortilin, Animals, Mice
Page Range:743-759
Date:July 2015
Official Publication:https://doi.org/10.1111/tra.12284
PubMed:View item in PubMed

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