CD40, an extracellular receptor for binding and uptake of Hsp70-peptide complexes.
Tumor and viral antigens elicit a potent immune response by heat shock protein-dependent uptake of antigenic peptide with subsequent presentation by MHC I. Receptors on antigen-presenting cells that specifically bind and internalize a heat shock protein-peptide complex have not yet been identified. Here, we show that cells expressing CD40, a cell surface protein crucial for B cell function and autoimmunity, specifically bind and internalize human Hsp70 with bound peptide. Binding of Hsp70-peptide complex to the exoplasmic domain of CD40 is mediated by the NH(2)-terminal nucleotide-binding domain of Hsp70 in its ADP state. The Hsp70 cochaperone Hip, but not the bacterial Hsp70 homologue DnaK, competes formation of the Hsp70-CD40 complex. Binding of Hsp70-ADP to CD40 is strongly increased in the presence of Hsp70 peptide substrate, and induces signaling via p38. We suggest that CD40 is a cochaperone-like receptor mediating the uptake of exogenous Hsp70-peptide complexes by macrophages and dendritic cells.
D000251:Adenosine Triphosphatases / Q000737:chemistry; D000818:Animals; D001667:Binding, Competitive; D019013:CD40 Antigens / Q000378:metabolism*; D002460:Cell Line; D003713:Dendritic Cells / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D049452:Green Fluorescent Proteins; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008164:Luminescent Proteins / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D048051:p38 Mitogen-Activated Protein Kinases
D019013:CD40 Antigens; D018840:HSP70 Heat-Shock Proteins; C105426:Hip chaperone; D008070:Lipopolysaccharides; D008164:Luminescent Proteins; D018832:Molecular Chaperones; D010446:Peptide Fragments; D049452:Green Fluorescent Proteins; D005982:Glutathione Transferase; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000251:Adenosine Triphosphatases