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J. Biol. Chem., Vol. 279, Issue 38, 39303-39309, September 17, 2004

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Inhibition of -Glucosidases I and II Increases the Cell Surface Expression of Functional Class A Macrophage Scavenger Receptor (SR-A) by Extending Its Half-life^*

Gang Tian, David Wilcockson, V. Hugh Perry, Pauline M. Rudd¶, Raymond A. Dwek¶, Frances M. Platt¶, and Nick Platt||**

From the Department of Cardiology, First Hospital, Xi'an Jiaotong University, Jiankang Road, Xi'an 710061, China, CNS Inflammation Group, Southampton Neurosciences Group, School of Biological Sciences, University of Southampton, Southampton SO16 7PX, United Kingdom, ^¶The Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom, and the ^||Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, United Kingdom

The class A scavenger receptor (SR-A) is a multifunctional trimeric membrane glycoprotein involved in atherogenesis. The mature receptor can mediate the binding and internalization of a number of specific ligands, including modified low-density lipoprotein. We have investigated the effects of inhibiting N-glycan processing on SR-A expression, distribution, and activity in the murine macrophage cell line RAW264.7. We have found that SR-A normally interacts with calnexin in the endoplasmic reticulum and in its mature form carries complex N-glycans. The imino sugar, N-butyldeoxynojirimycin (NB-DNJ) is an inhibitor of the N-glycan processing enzymes -glucosidases I and II. Following NB-DNJ treatment SR-A became Endo H-sensitive, consistent with inhibition of N-glycan processing. A dose-dependent increase in cell surface expression of SR-A was observed in response to NB-DNJ treatment. The receptor on inhibitor-treated cells was still functional because the increased surface expression resulted in a proportional enhancement in the endocytosis of the ligand, acetylated low-density lipoprotein. The expression of SR-A on NB-DNJ cultured cells was further enhanced by co-treatment with interferon-. Quantitative reverse transcriptase-PCR analysis did not show a significant difference in the amount of SR-A mRNA in NB-DNJ-treated RAW264.7 cells. However, the half-life of SR-A protein was significantly increased. These data indicate the retention of glucosylated N-glycans does not result in gross misfolding and degradation of this receptor or prevent its transport to the cell surface. SR-A interacts with calnexin and when the association is prevented changes in the recycling kinetics and rate of turnover of the receptor result, leading to enhanced cell surface expression.

Received for publication, May 11, 2004 , and in revised form, July 2, 2004.

^* This work was supported by a NATO/FCO Chevening Postdoctoral Fellowship from The Royal Society. 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.

^** To whom correspondence should be addressed: Dept. of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, United Kingdom. Tel.: 44-1865-272158; Fax: 44-1865-272420; E-mail: nick.platt{at}anat.ox.ac.uk.

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