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Journal of Lipid Research, Vol. 49, 1312-1321, June 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Glycosylation of Asn-76 in mouse GPIHBP1 is critical for its appearance on the cell surface and the binding of chylomicrons and lipoprotein lipase

Anne P. Beigneux^1,*, Peter Gin^*, Brandon S. J. Davies^*, Michael M. Weinstein^*,, André Bensadoun, Robert O. Ryan^**, Loren G. Fong^* and Stephen G. Young^1,*,

^* Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095
Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095
Division of Nutritional Science, Cornell University, Ithaca, NY 14853
^** Children's Hospital Oakland Research Institute, Oakland, CA 94609

This work was supported by a Scientist Development Award from the American Heart Association, National Office (to A.P.B.), BayGenomics (HL66621 and HL66600), R01 HL087228 (to S.G.Y.), and HL073061 (to R.O.R.).

Published, JLR Papers in Press, March 13, 2008.

¹ To whom correspondence should be addressed. e-mail: abeigneux{at}mednet.ucla.edu (A.P.B.); sgyoung{at}mednet.ucla.edu (S.G.Y.)

GPIHBP1 is a glycosylphosphatidylinositol-anchored protein in the lymphocyte antigen 6 (Ly-6) family that recently was identified as a platform for the lipolytic processing of triglyceride-rich lipoproteins. GPIHBP1 binds both LPL and chylomicrons and is expressed on the luminal face of microvascular endothelial cells. Here, we show that mouse GPIHBP1 is N-glycosylated at Asn-76 within the Ly-6 domain. Human GPIHBP1 is also glycosylated. The N-linked glycan could be released from mouse GPIHBP1 with N-glycosidase F, endoglycosidase H, or endoglycosidase F1. The glycan was marginally sensitive to endoglycosidase F2 digestion but resistant to endoglycosidase F3 digestion, suggesting that the glycan on GPIHBP1 is of the oligomannose type. Mutating the N-glycosylation site in mouse GPIHBP1 results in an accumulation of GPIHBP1 in the endoplasmic reticulum and a markedly reduced amount of the protein on the cell surface. Consistent with this finding, cells expressing a nonglycosylated GPIHBP1 lack the ability to bind LPL or chylomicrons. Eliminating the N-glycosylation site in a truncated soluble version of GPIHBP1 causes a modest reduction in the secretion of the protein. These studies demonstrate that N-glycosylation of GPIHBP1 is important for the trafficking of GPIHBP1 to the cell surface.

Supplementary key words glycosylphosphatidylinositol-anchored HDL binding protein 1 • knockout mice • chylomicronemia • hypertriglyceridemia

Abbreviations: DMPC, dimyristoylphosphatidylcholine; ER, endoplasmic reticulum; GPI, glycosylphosphatidylinositol; GPIHBP1, glycosylphosphatidylinositol-anchored HDL binding protein 1; PIPLC, phosphatidylinositol-specific phospholipase C; PNGase F, N-glycosidase F; sGPIHBP1, truncated soluble GPIHBP1; UPAR, urokinase-type plasminogen activator receptor

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				A. P. Beigneux, B. S. J. Davies, A. Bensadoun, L. G. Fong, and S. G. Young GPIHBP1, a GPI-anchored protein required for the lipolytic processing of triglyceride-rich lipoproteins J. Lipid Res., April 1, 2009; 50(Supplement): S57 - S62. [Abstract] [Full Text] [PDF]