title: Disruption of the association of 73 kDa heat shock cognate protein with transporters associated with antigen processing (TAP) decreases TAP-dependent translocation of antigenic peptides into the endoplasmic reticulum.
abstract: Major histocompatibility complex class I-bound antigenic peptides generated in the cytosol are translocated into the ER by TAP. In the present study, the physical association of HSC73 with TAP in human lymphoblastoid T1 cells was demonstrated. The dissociation was induced in the presence of 10 mM ATP, indicating that the ADP-binding form of HSC73 might be associated with TAP. We found that HSC73-binding immunosuppressant, MeDSG disrupted the HSC73-TAP association, whereas it did not affect the binding of HSC73 to a substrate protein. MHC class I expression on the cell surface was also downregulated. Then, the effect of MeDSG on the TAP-mediated ER translocation was examined using two homologous model peptides, NGT-Bw4 and NGT-Bw6, which had distinct binding affinity to HSC73. Although high-affinity peptide NGT-Bw4 was translocated by TAP, low-affinity peptide NGT-Bw6 was not. The TAP-dependent translocation of NGT-Bw4 was abolished in the presence of MeDSG. Decreased presentation on the cell surface was shown for the human leukocyte antigen (HLA)-A31-restricted natural antigenic peptide F4.2, which had high affinity to HSC73, in the presence of MeDSG. It was indicated that disruption of the HSC73-TAP association resulted in inhibition of TAP-dependent translocation of HSC73-bound peptides. Our findings highlighted an important role of HSC73 for feeding antigenic peptides to TAP, and suggested a possibility that a synthetic polyamine might inhibit the function of HSC73, thereby suppressing MHC class I-restricted presentation of HSC73-bound antigenic peptides.
authors.affiliation: Third Department of Internal Medicine, Asahikawa Medical College, Asahikawa, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kamiguchi
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Torigoe
authors.forename: Osamutaro
authors.initials: O
authors.lastname: Fujiwara
authors.forename: Shin
authors.initials: S
authors.lastname: Ohshima
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Hirohashi
authors.forename: Hiroeki
authors.initials: H
authors.lastname: Sahara
authors.forename: Itaru
authors.initials: I
authors.lastname: Hirai
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kohgo
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Sato
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D017951:Antigen Presentation; D000941:Antigens / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006146:Guanidines / Q000494:pharmacology; D050883:HSC70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D010455:Peptides / Q000378:metabolism*; D011485:Protein Binding
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D000941:Antigens; D006146:Guanidines; D050883:HSC70 Heat-Shock Proteins; C494371:HSPA8 protein, human; D015395:Histocompatibility Antigens Class I; D007166:Immunosuppressive Agents; D010455:Peptides; C073119:TAP1 protein, human; C076911:methyldeoxyspergualin