International Immunology, Vol. 8, No. 5, pp. 625-640,May 1996
© 1996 Japanese Society for Immunology
HLA-DM and MHC class II molecules co-distribute with peptidase-containing lysosomal subcompartments
Department of Cellular Biochemistry, The Netherlands Cancer Institute Plesmanlaan 121, 1066CX Amsterdam, The Netherlands
1 Human Immunogenetics Laboratory, Imperial Cancer Research Fund London WC2A 3PX, UK
2 Department of Cell Biology, Amsterdam Medical Center 1015 AZ Amsterdam, The Netherlands
Correspondence to: Correspondence to: J. Neefjes
MHC class II molecules associate with peptides in the endocytic pathway. Different endosomal locations for peptide loading of class II molecules, varying from early endosomes (EE) to lysosomes, have been assigned on the basis of subcellular fractionation experiments. We have determined the intracellular location of HLA-DM, a molecule that supports peptide loading of class II molecules, by separating vesicles from the melanoma cell line Mel JuSo on the basis of buoying density and surface charge. In both fractionations, HLA-DM co-fractionated with a lysosomal compartment containing ß-hexosaminidase (ß-hex) activity and not with endosomes. Further analysis showed that HLA-DM mainly co-fractionated with a sub-lysosomal structure characterized by a relative low density and containing both pro- and mature cathepsin D and MHC class II molecules. Fluid phase markers first enter this compartment before entering high-density lysosomes that contain exclusively mature cathepsin D, some HLA-DM and no detectable MHC class II molecules. Finally we determined the intracellular location of neutral and acidic peptidases. Whereas neutral peptidase activity was detected in the endoplasmic reticulum and/or plasma membrane fractions, acidic peptidase activity exclusively migrated at the position of HLA-DM containing lysosomal vesicles. Our results show that class II molecules co-migrate with HLA-DM, pro- and mature cathepsin D, ß-hex and acidic peptidase activity. HLA-DM, cathepsin D and class II molecules were not observed at the position of EE. Our data suggest that HLA-DM-mediated peptide loading of class II molecules occurs in a lysosomal subcompartment.
Keywords: HLA-DM, lysosomes, MHC class II molecules, peptidases
revised 31 October 1995, accepted 8 January 1996.
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