Hsp90alpha chaperones large C-terminally extended proteolytic intermediates in the MHC class I antigen processing pathway.
Intracellular proteins are degraded in the antigen processing pathway to generate peptide-loaded MHC I complexes (pMHC I) for immune surveillance. The characteristics of the final pMHC I are clear but those of their precursors and their potential binding partners remain poorly defined. By using a unique method to biochemically detect preprocessed ovalbumin-derived antigenic peptides, we find that cells generate large, C-terminally extended proteolytic intermediates that are associated with the alpha isotype of hsp90 chaperone. Knockdown of hsp90alpha expression by siRNA resulted in the loss of these intermediates and decreased presentation of the final pMHC I on the cell surface. Generation of pMHC I was also inhibited by knockdown of the cochaperone CHIP that interacts with heat shock proteins, ubiquitinates their clients, and delivers them to the proteasome. Thus, hsp90alpha can serve as a chaperone for precursors of pMHC I at an early stage in the antigen processing pathway.
Kunisawa
Jun
J
Division of Immunology, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California 94720, USA.
Shastri
Nilabh
N
D017951:Antigen Presentation / Q000276:immunology*; D000941:Antigens / Q000276:immunology / Q000378:metabolism*; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D018841:HSP90 Heat-Shock Proteins / Q000276:immunology*; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D047468:Immunoprecipitation; D046988:Proteasome Endopeptidase Complex / Q000276:immunology / Q000378:metabolism; D034741:RNA, Small Interfering; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000276:immunology
D000941:Antigens; D018841:HSP90 Heat-Shock Proteins; D015395:Histocompatibility Antigens Class I; D034741:RNA, Small Interfering; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex