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Journal of Lipid Research, Vol. 44, 1821-1832, October 2003
Copyright © 2003 by American Society for Biochemistry and Molecular Biology

Distribution and trafficking of MPR300 is normal in cells with cholesterol accumulated in late endocytic compartments

Atsushi Umeda, Hideaki Fujita, Toshio Kuronita, Kaori Hirosako, Masaru Himeno and Yoshitaka Tanaka¹

Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan

¹ To whom correspondence should be addressed. e-mail: tanakay{at}bioc.phar.kyushu-u.ac.jp

It has been reported that an accumulation of cholesterol within late endosomes/lysosomes in Niemann-Pick type C (NPC) fibroblasts and U18666A-treated cells causes impairment of retrograde trafficking of the cation-independent mannose 6-phosphate/IGF-II receptor (MPR300) from late endosomes to the trans-Golgi network (TGN). In apparent conflict with these results, here we show that as in normal fibroblasts, MPR300 localizes exclusively to the TGN in NPC fibroblasts as well as in normal fibroblasts treated with U18666A. This localization can explain why several lysosomal properties and functions, such as intracellular lysosomal enzyme activity and localization, the biosynthesis of cathepsin D, and protein degradation, are all normal in NPC fibroblasts. These results, therefore, suggest that the accumulation of cholesterol in late endosomes/lysosomes does not affect the retrieval of MPR300 from endosomes to the TGN. Furthermore, treatment of normal and NPC fibroblasts with chloroquine, which inhibits membrane traffic from early endosomes to the TGN, resulted in a redistribution of MPR300 to EEA1 and internalized transferrin-positive, but LAMP-2-negative, early-recycling endosomes.

We propose that in normal and NPC fibroblasts, MPR300 is exclusively targeted from the TGN to early endosomes, from where it rapidly recycles back to the TGN without being delivered to late endosomes. This notion provides important insights into the definition of late endosomes, as well as the biogenesis of lysosomes.

Abbreviations: EGF, epidermal growth factor; EGFR, EGF receptor; GFP, green fluorescence protein; GGA, Golgi-associated, -adaptin-homologous, ARF-interacting protein; LBPA, lysobisphosphatidic acid; MPR, mannose 6-phosphate receptor; MPR46, cation-dependent mannose 6-phosphate receptor; MPR300, cation-independent mannose 6-phosphate/IGF-II receptor; MVB, multivesicular body; NPC, Niemann-Pick type C; PACS-1, phosphofurin acidic cluster sorting protein-1; STxB, Shiga toxin B; Tfn, transferrin; TGN, trans-Golgi network

Supplementary key words Niemann-Pick type C fibroblasts • endosomes • lysosomes • intracellular trafficking • trans-Golgi network • cation-independent mannose 6-phosphate/IGF-II receptor

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