Reduced cell surface expression of HLA-C molecules correlates with restricted peptide binding and stable TAP interaction.
HLA-C molecules are poorly expressed at the cell surface compared with HLA-A and HLA-B locus products. The reason for the low surface expression and the underlying mechanism is unclear. We show that the HLA-C4 allele is expressed intracellularly in amounts similar to HLA-A and HLA-B alleles. However, the majority of the HLA-C4 molecules is not transported, but is retained in the endoplasmic reticulum by stable interaction with TAP. This pool does not appear to participate in the formation of HLA-C4/peptide complexes, but is degraded in the endoplasmic reticulum. HLA-C4 molecules can dissociate from TAP upon binding of specific peptide. However, they require a 10-fold higher concentration of a completely degenerated 9-mer peptide mixture for release from TAP than the HLA-A and HLA-B alleles. Our data show that the HLA-C molecules tested are more selective in their peptide binding than HLA-A and HLA-B molecules, resulting in prolonged association with TAP and a reduced formation of intracellular HLA-C/peptide complexes. The restricted peptide binding of certain HLA-C alleles provides one explanation for the reduced expression of HLA-C molecules at the cell surface. Other mechanisms will be discussed.
Neisig
A
A
Department of Cellular Biochemistry, The Netherlands Cancer Institute, Amsterdam.
Melief
C J
CJ
Neefjes
J
J
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000483:Alleles; D001402:B-Lymphocytes / Q000378:metabolism* / Q000648:ultrastructure; D001667:Binding, Competitive; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015236:HLA-C Antigens / Q000378:metabolism*; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D011485:Protein Binding
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D015236:HLA-C Antigens; D010455:Peptides; C073119:TAP1 protein, human