IRAP identifies an endosomal compartment required for MHC class I cross-presentation.
Major histocompatibility complex (MHC) class I molecules present peptides, produced through cytosolic proteasomal degradation of cellular proteins, to cytotoxic T lymphocytes. In dendritic cells, the peptides can also be derived from internalized antigens through a process known as cross-presentation. The cellular compartments involved in cross-presentation remain poorly defined. We found a role for peptide trimming by insulin-regulated aminopeptidase (IRAP) in cross-presentation. In human dendritic cells, IRAP was localized to a Rab14+ endosomal storage compartment in which it interacted with MHC class I molecules. IRAP deficiency compromised cross-presentation in vitro and in vivo but did not affect endogenous presentation. We propose the existence of two pathways for proteasome-dependent cross-presentation in which final peptide trimming involves IRAP in endosomes and involves the related aminopeptidases in the endoplasmic reticulum.
Saveanu
Loredana
L
INSERM, U580, 75015 Paris, France; Université Paris Descartes, Faculté de Médecine René Descartes, 75015 Paris, France.
Carroll
Oliver
O
Weimershaus
Mirjana
M
Guermonprez
Pierre
P
Firat
Elke
E
Lindo
Vivian
V
Greer
Fiona
F
Davoust
Jean
J
Kratzer
Roland
R
Keller
Susanna R
SR
Niedermann
Gabriele
G
van Endert
Peter
P
D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045142:Cross-Priming; D010122:Cystinyl Aminopeptidase / Q000378:metabolism*; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D011992:Endosomes / Q000201:enzymology*; D000939:Epitopes; D006680:HLA Antigens / Q000276:immunology / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010587:Phagocytosis; D010588:Phagosomes / Q000201:enzymology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D013379:Substrate Specificity
D000939:Epitopes; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D010122:Cystinyl Aminopeptidase; C105964:leucyl-cystinyl aminopeptidase; D046988:Proteasome Endopeptidase Complex