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J. Biol. Chem., Vol. 281, Issue 17, 12081-12092, April 28, 2006

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The Lipoprotein Receptor-related Protein-1 (LRP) Adapter Protein GULP Mediates Trafficking of the LRP Ligand Prosaposin, Leading to Sphingolipid and Free Cholesterol Accumulation in Late Endosomes and Impaired Efflux^*

Robert S. Kiss¹, Zhong Ma, Kumiko Nakada-Tsukui, Enrico Brugnera, Gerard Vassiliou, Heidi M. McBride, Kodi S. Ravichandran², and Yves L. Marcel³

From the Lipoprotein and Atherosclerosis Research Group, Department of Pathology and Laboratory Medicine and Department of Biochemistry, Microbiology and Immunology, University of Ottawa Heart Institute, Ottawa K1Y 4W7, Canada and Carter Immunology Center and the Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908

One of the conserved functional pathways linked to engulfment of apoptotic corpses involves two membrane proteins low density lipoprotein receptor-related protein-1 (LRP) and ABCA1 and the LRP adapter protein GULP. Because LRP and ABCA1 play roles in cellular lipid trafficking and efflux, here we addressed whether the third member, the LRP adapter protein GULP, also affects cellular lipid transport. Several lines of evidence show that overexpression of GULP causes glycosphingolipid and free cholesterol accumulation in the late endosome/lysosome compartment that is accompanied by down-regulation of ABCA1 and decreased efflux. Conversely, knockdown of endogenous GULP expression promoted cholesterol flux through the late endosomes and up-regulation of ABCA1, even in the context of a disease state such as Niemann-Pick Type C disease. Mechanistically, we were able to show that trafficking of the LRP ligands ₂-macroglobulin and prosaposin, a protein cofactor necessary for glycosphingolipid degradation, are impaired in cells expressing full-length GULP protein, resulting in glycosphingolipid and free cholesterol accumulation in the late endosome/lysosome compartment. On the other hand, knockdown of endogenous GULP results in enhanced targeting of prosaposin and enhanced clearance of glycosphingolipids and cholesterol from the late endosomes. Taken together, these data reveal that GULP/LRP/ABCA1 represents a triad of molecules involved in engulfment and cellular lipid homeostasis.

Received for publication, January 20, 2006 , and in revised form, February 22, 2006.

^* This work was supported in part by a American Cancer Society award, National Institutes of Health Grant GM-069998 (to K. S. R.), a Heart and Stroke Foundation of Canada research grant, and a Canadian Institutes of Health Research group grant (to H. M. M. and Y. L. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Figs. 1, 2, 3, 4, 5, 6 and a movie.

¹ Supported by a research fellowship from the Heart and Stroke Foundation of Canada.

This work is dedicated to the memory of our colleague and friend, Gerard Vassiliou, who passed away May 10, 2005.

² To whom correspondence may be addressed: Carter Immunology Center, University of Virginia, MR4-Rm. 4072D, Box 801386, Lane Rd., Charlottesville, VA 22908. Tel.: 434-243-6093; Fax: 434-924-1221; E-mail: Ravi{at}virginia.edu.

³ To whom correspondence may be addressed: Lipoprotein and Atherosclerosis Research Group, University of Ottawa Heart Institute, 40 Ruskin St., H455, Ottawa, Ontario, K1Y4W7. Tel.: 613-761-5255; Fax: 613-761-5281; E-mail: ylmarcel{at}ottawaheart.ca.

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