Differential sorting of lysosomal enzymes in mannose 6-phosphate receptor-deficient fibroblasts.

Abstract

In higher eukaryotes, the transport of soluble lysosomal enzymes involves the recognition of their mannose 6‐phosphate signal by two receptors: the cation‐independent mannose 6‐phosphate/insulin‐like growth factor II receptor (CI‐MPR) and the cation‐dependent mannose 6‐phosphate receptor (CD‐MPR). It is not known why these two different proteins are present in most cell types. To investigate their relative function in lysosomal enzyme targeting, we created cell lines that lack either or both MPRs. This was accomplished by mating CD‐MPR‐deficient mice with Thp mice that carry a CI‐MPR deleted allele. Fibroblasts prepared from embryos that lack the two receptors exhibit a massive missorting of multiple lysosomal enzymes and accumulate undigested material in their endocytic compartments. Fibroblasts that lack the CI‐MPR, like those lacking the CD‐MPR, exhibit a milder phenotype and are only partially impaired in sorting. This demonstrates that both receptors are required for efficient intracellular targeting of lysosomal enzymes. More importantly, comparison of the phosphorylated proteins secreted by the different cell types indicates that the two receptors may interact in vivo with different subgroups of hydrolases. This observation may provide a rational explanation for the existence of two distinct mannose 6‐phosphate binding proteins in mammalian cells.

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

“…Acid hydrolase can also reach endolysosomes after endocytosis by the cation-independent MPR. In the absence of UDP-GlcNAc:lysosomal enzyme GlcNAc-1-phosphotransferase (also known as GlcNAc-1-phosphotransferase; hereafter Ptase) (the first enzyme involved in Man-6-P synthesis), or upon knockdown of MPRs, fibroblasts and other cells of mesenchymal origin, as well as acinar secretory cells, missort their acid hydrolases, causing lysosomal dysfunction (Ludwig et al, 1994;Pohlmann et al, 1995;Kornfeld and Sly, 2000;Boonen et al, 2011). However, intriguingly, the aspartic protease cathespin D can still reach lysosomes in several cell types (Rijnboutt et al, 1991;Glickman and Kornfeld, 1993;Dittmer et al, 1999;Pohl et al, 2010;van Meel et al, 2011;Markmann et al, 2015).…”

The 46-kDa mannose 6-phosphate receptor does not depend on endosomal acidification for delivery of hydrolases to lysosomes

“…Mice deficient in MPR46 and/or M6P/IGF2R have been generated (Köster et al, 1993;Ludwig et al, 1993;Ludwig et al, 1994). Studies on MPR46-and/or M6P/IGF2R-negative fibroblasts have indicated that both receptors are necessary for efficient lysosomal targeting.…”

The mannose 6‐phosphate/insulin‐like growth factor II receptor restricts the tumourigenicity and invasiveness of squamous cell carcinoma cells

“…[8][9][10] Lysosomal sorting via M6P/IGF2R is generally far more efficient than by MPR46, demonstrating that the former is the main lysosomal targeting receptor in mammalian cells. 11,12 However, M6P/IGF2R also binds a variety of other factors that impinge on the proliferation, migration and invasiveness of tumour cells, including insulin-like growth factor II (IGF-II), 13 transforming growth factor b, 14 urokinase-type plasminogen activator receptor 15 and plasminogen. 16 Hence, it is of high relevance that the M6P/IGF2R gene is frequently inactivated in human and animal tumours.…”