Tapasin enhances peptide-induced expression of H2-M3 molecules, but is not required for the retention of open conformers.

Lybarger L, Yu YY, Chun T, Wang CR, Grandea AG, Van Kaer L, Hansen TH
J Immunol. 2001 167 (4): 2097-105

PMID: 11489993 · DOI:10.4049/jimmunol.167.4.2097

H2-M3 is a class Ib MHC molecule that binds a highly restricted pool of peptides, resulting in its intracellular retention under normal conditions. However, addition of exogenous M3 ligands induces its escape from the endoplasmic reticulum (ER) and, ultimately, its expression at the cell surface. These features of M3 make it a powerful and novel model system to study the potentially interrelated functions of the ER-resident class I chaperone tapasin. The functions ascribed to tapasin include: 1) ER retention of peptide-empty class I molecules, 2) TAP stabilization resulting in increased peptide transport, 3) direct facilitation of peptide binding by class I, and 4) peptide editing. We report in this study that M3 is associated with the peptide-loading complex and that incubation of live cells with M3 ligands dramatically decreased this association. Furthermore, high levels of open conformers of M3 were efficiently retained intracellularly in tapasin-deficient cells, and addition of exogenous M3 ligands resulted in substantial surface induction that was enhanced by coexpression of either membrane-bound or soluble tapasin. Thus, in the case of M3, tapasin directly facilitates intracellular peptide binding, but is not required for intracellular retention of open conformers. As an alternative approach to define unique aspects of M3 biosynthesis, M3 was expressed in human cell lines that lack an M3 ortholog, but support expression of murine class Ia molecules. Unexpectedly, peptide-induced surface expression of M3 was observed in only one of two cell lines. These results demonstrate that M3 expression is dependent on a unique factor compared with class Ia molecules.

MeSH Terms (22)

Adjuvants, Immunologic Animals Antiporters ATP-Binding Cassette Transporters ATP Binding Cassette Transporter, Subfamily B, Member 2 ATP Binding Cassette Transporter, Subfamily B, Member 3 Cell Line, Transformed Epitopes H-2 Antigens HeLa Cells Histocompatibility Antigen H-2D Histocompatibility Antigens Class I Humans Immunoglobulins L Cells Membrane Transport Proteins Mice Mutagenesis, Site-Directed Peptides Protein Binding Protein Conformation Transfection

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