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The DM and DM Chain Cooperate in the Oxidation and Folding of HLA-DM¹

Department of Biological Sciences, University of Durham, Durham, United Kingdom

HLA-DM (DM) is a heterodimeric MHC molecule that catalyzes the peptide loading of classical MHC class II molecules in the endosomal/lysosomal compartments of APCs. Although the function of DM is well-established, little is known about how DM and -chains fold, oxidize, and form a complex in the endoplasmic reticulum (ER). In this study, we show that glycosylation promotes, but is not essential for, DM ER exit. However, glycosylation of DM N15 is required for oxidation of the -chain. The DM and -chains direct each others fate: single DM chains cannot fully oxidize without DM, while DM forms disulfide-linked homodimers without DM. Correct oxidation and subsequent ER egress depend on the unique DM C25 and C35 residues. This suggests that the C25-C35 disulfide bond in the peptide-binding domain overcomes the need for stabilizing peptides required by other MHC molecules.

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.

¹ This work was supported by a Marie Curie fellowship and the Biotechnology and Biological Sciences Research Council.

² Address correspondence and reprint requests to Dr. Adam M. Benham, Department of Biological Sciences, University of Durham, South Road, Durham, DH1 3LE, U.K. E-mail address: adam.benham{at}durham.ac.uk

³ Abbreviations used in this paper: ER, endoplasmic reticulum; Ii, invariant chain; HA, hemagglutinin; IAA, iodoacetic acid; endoH, endoglycosidase H; NEM, N-ethylmaleimide.