Critical role for the tapasin-docking site of TAP2 in the functional integrity of the MHC class I-peptide-loading complex.
The transporter associated with Ag processing (TAP) translocates antigenic peptides into the endoplasmic reticulum for binding onto MHC class I (MHC I) molecules. Tapasin organizes a peptide-loading complex (PLC) by recruiting MHC I and accessory chaperones to the N-terminal regions (N domains) of the TAP subunits TAP1 and TAP2. To investigate the function of the tapasin-docking sites of TAP in MHC I processing, we expressed N-terminally truncated variants of TAP1 and TAP2 in combination with wild-type chains, as fusion proteins or as single subunits. Strikingly, TAP variants lacking the N domain in TAP2, but not in TAP1, build PLCs that fail to generate stable MHC I-peptide complexes. This correlates with a substantially reduced recruitment of accessory chaperones into the PLC demonstrating their important role in the quality control of MHC I loading. However, stable surface expression of MHC I can be rescued in post-endoplasmic reticulum compartments by a proprotein convertase-dependent mechanism.
Leonhardt
Ralf M
RM
University of Cologne, Institute for Genetics, Cologne, Germany.
Keusekotten
Kirstin
K
Bekpen
Cemalettin
C
Knittler
Michael R
MR
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017920:Antiporters / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D006680:HLA Antigens / Q000378:metabolism / Q000502:physiology*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D009154:Mutation; D010455:Peptides / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D017920:Antiporters; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D007136:Immunoglobulins; D026901:Membrane Transport Proteins; D010455:Peptides; C073119:TAP1 protein, human; C107762:tapasin; C071692:TAP2 protein, human