The 46-kDa mannose 6-phosphate receptor does not depend on endosomal acidification for delivery of hydrolases to lysosomes.
In mammalian cells, the mannose 6-phosphate receptor pathway accounts for the transport of most soluble acid hydrolases to lysosomes. It is believed that dissociation of mannose 6-phosphate receptors and their ligands is entirely driven by the acidic environment in endosomal compartments. Indeed, pH-perturbing substances such as ammonium chloride and monensin have been shown to inhibit lysosomal enzyme targeting in cells that express both known mannose 6-phosphate receptors. We now demonstrate that ammonium chloride and monensin exert modest effects on the intracellular retention of lysosomal hydrolases in murine cells that synthesize only the 46-kDa mannose 6-phosphate receptor. Neither ammonium chloride nor monensin induces changes to the subcellular localization of lysosomal hydrolases and the 46-kDa mannose 6-phosphate receptor in these cells. This suggests that endosomal dissociation of the receptor and its ligands still occurs in the presence of these agents. We conclude that the murine 46-kDa mannose 6-phosphate receptor has the capacity to deliver its cargo proteins to lysosomes even in the absence of endosomal acidification.
Probst
Olivia C
OC
Institut für Angewandte Genetik und Zellbiologie, Universität für Bodenkultur Wien, Muthgasse 18, 1190 Vienna, Austria.
Ton
Phuong
P
Svoboda
Barbara
B
Gannon
Andrew
A
Schuhmann
Werner
W
Wieser
Johannes
J
Pohlmann
Regina
R
Mach
Lukas
L
D041721:3T3-L1 Cells; D000818:Animals; D002401:Cathepsin B / Q000378:metabolism; D002402:Cathepsin D / Q000378:metabolism; D056668:Cathepsin L; D002403:Cathepsins / Q000378:metabolism; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism; D011992:Endosomes / Q000737:chemistry*; D006031:Glycosylation; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006867:Hydrolases / Q000378:metabolism*; D007476:Ionophores / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D008985:Monensin / Q000494:pharmacology; D041681:NIH 3T3 Cells; D021381:Protein Transport / Q000187:drug effects; D017527:Receptor, IGF Type 2 / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014018:Tissue Distribution
D007476:Ionophores; D017527:Receptor, IGF Type 2; D008985:Monensin; D006867:Hydrolases; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L; C534278:Ctsl protein, mouse; D002402:Cathepsin D