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Vol. 16, Issue 8, 3873-3886, August 2005
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* Institutes of Biomedicine, University of Helsinki, 00014 Helsinki, Finland;
Institutes of Biotechnology, University of Helsinki, 00014 Helsinki, Finland;
Département de Pathologie Moléculaire, Institut de Genetique et de Biologie Moleculaire et Cellulaire, 67404 Illkirch, Communauté Urbaine de Strasbourg, France; and
National Public Health Institute, 00300 Helsinki, Finland
Submitted December 22, 2004;
Revised April 30, 2005;
Accepted May 24, 2005
Monitoring Editor: Howard Riezman
MLN64 is a late endosomal cholesterol-binding membrane protein of an unknown function. Here, we show that MLN64 depletion results in the dispersion of late endocytic organelles to the cell periphery similarly as upon pharmacological actin disruption. The dispersed organelles in MLN64 knockdown cells exhibited decreased association with actin and the Arp2/3 complex subunit p34-Arc. MLN64 depletion was accompanied by impaired fusion of late endocytic organelles and delayed cargo degradation. MLN64 overexpression increased the number of actin and p34-Arc-positive patches on late endosomes, enhanced the fusion of late endocytic organelles in an actin-dependent manner, and stimulated the deposition of sterol in late endosomes harboring the protein. Overexpression of wild-type MLN64 was capable of rescuing the endosome dispersion in MLN64-depleted cells, whereas mutants of MLN64 defective in cholesterol binding were not, suggesting a functional connection between MLN64-mediated sterol transfer and actin-dependent late endosome dynamics. We propose that local sterol enrichment by MLN64 in the late endosomal membranes facilitates their association with actin, thereby governing actin-dependent fusion and degradative activity of late endocytic organelles.
Abbreviations used: CytD, cytochalasin D; DHE, dehydroergosterol; DiI-LDL, 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine-perchlorate-labeled low density lipoprotein; EGF, epidermal growth factor; LBPA, lysobisphosphatidic acid; LDL, low-density lipoprotein; LPDS, lipoprotein-deficient serum; NPC, Niemann-Pick type C; PEG, polyethylene glycol; StAR, steroidogenic acute regulatory protein; START, StAR-related lipid transfer domain.
The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).
Address correspondence to: Elina Ikonen (elina.ikonen{at}helsinki.fi).
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