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Disrupts Antigen Presentation Without Altering Endosomal Localization1
*
School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
Department of Pediatrics, Stanford University Medical Center, Stanford, CA 94305;
Department of Medicine, North Shore University Hospital-New York University School of Medicine, Manhasset, NY 11030; and
§
Virginia Mason Research Center, Seattle, WA 98101
The HLA-DR hemizygous B lymphoblastoid cell line, 10.24.6, has a
DRA mutation (Pro96
Ser) that creates a novel
glycosylation site at Asn94. The mutant DR molecules are
primarily associated with nested fragments of invariant chain (class
II-associated invariant chain peptides), and their interaction with
HLA-DM is impaired. Here we further analyzed the defect in 10.24.6
cells. Expressing Ser96 mutant DRA cDNA in DRA-null cells
recapitulated the 10.24.6 phenotype, indicating that the mutation
causes the Ag presentation defect. A mutation to Ala96
,
which does not introduce an extra glycan, generated a normal phenotype;
the critical role of the glycan was further supported by experiments in
which N-glycosylation was blocked by tunicamycin. We also
evaluated whether the 10.24.6 mutation affected DR3 maturation or
trafficking. Metabolic labeling and subcellular fractionation showed
that assembly, endosomal transport, and invariant chain proteolysis of
mutant DR3 molecules were similar to wild-type. A slight delay in
export from the endoplasmic reticulum to the Golgi apparatus in 10.24.6
cells probably did not contribute significantly to the Ag presentation
defect, because the abundance of DM and mutant DR in peptide-loading
compartments was normal at steady state. Our results indicate that
proper localization of these molecules does not depend on their
interaction.
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