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Originally published In Press as doi:10.1074/jbc.M005112200 on August 29, 2000

J. Biol. Chem., Vol. 275, Issue 47, 37062-37071, November 24, 2000
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Functional Characterization of a Lysosomal Sorting Motif in the Cytoplasmic Tail of HLA-DObeta *

Alexandre BrunetDagger §, Angela Samaan§, Francis DeshaiesDagger §||, Thomas J. Kindt, and Jacques ThibodeauDagger **

From the Dagger  Laboratoire d'Immunologie Moléculaire, Département de Microbiologie et Immunologie, Université de Montréal, Québec H3C 3J7, Canada and the  Laboratory of Immunogenetics, NIAID, National Institutes of Health, Bethesda, Maryland 20892

HLA-DO is an intracellular non-classical class II major histocompatibility complex molecule expressed in the endocytic pathway of B lymphocytes, which regulates the loading of antigenic peptides onto classical class II molecules such as HLA-DR. The activity of HLA-DO is mediated through its interaction with the peptide editor HLA-DM. Here, our results demonstrate that although HLA-DO is absolutely dependent on its association with DM to egress the endoplasmic reticulum, the cytoplasmic portion of its beta  chain encodes a functional lysosomal sorting signal. By confocal microscopy and flow cytometry analysis, we show that reporter transmembrane molecules fused to the cytoplasmic tail of HLA-DObeta accumulated in Lamp-1+ vesicles of transfected HeLa cells. Mutagenesis of a leucine-leucine motif abrogated lysosomal accumulation and resulted in cell surface redistribution of reporter molecules. Finally, we show that mutation of the di-leucine sequence in DObeta did not alter its lysosomal sorting when associated with DM molecules. Taken together, these results demonstrate that lysosomal expression of the DO-DM complex is mediated primarily by the tyrosine-based motif of HLA-DM and suggest that the DObeta -encoded motif is involved in the fine-tuning of the intracellular sorting.

* This work was supported in part by grants from the Medical Research Council of Canada (to J. T.) and the Cancer Research Society Inc.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ These authors contributed equally to this work.

|| Scholar of the Fonds des Chercheurs et Aides à la Recherche.

** Supported by a scholarship from the Medical Research Council of Canada. To whom correspondence should be addressed: Laboratoire d'Immunologie Moléculaire Département de Microbiologie et Immunologie, Université de Montréal, CP 6128, Succ. Centre-Ville, Montréal, Québec H3C 3J7, Canada. Tel.: 514-343-6279; Fax: 514-343-5701; E-mail: thibodj@magellan.umontreal.ca.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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