title: IRAP identifies an endosomal compartment required for MHC class I cross-presentation.
abstract: 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.
authors.affiliation: INSERM, U580, 75015 Paris, France; Université Paris Descartes, Faculté de Médecine René Descartes, 75015 Paris, France.
authors.forename: Loredana
authors.initials: L
authors.lastname: Saveanu
authors.forename: Oliver
authors.initials: O
authors.lastname: Carroll
authors.forename: Mirjana
authors.initials: M
authors.lastname: Weimershaus
authors.forename: Pierre
authors.initials: P
authors.lastname: Guermonprez
authors.forename: Elke
authors.initials: E
authors.lastname: Firat
authors.forename: Vivian
authors.initials: V
authors.lastname: Lindo
authors.forename: Fiona
authors.initials: F
authors.lastname: Greer
authors.forename: Jean
authors.initials: J
authors.lastname: Davoust
authors.forename: Roland
authors.initials: R
authors.lastname: Kratzer
authors.forename: Susanna R
authors.initials: SR
authors.lastname: Keller
authors.forename: Gabriele
authors.initials: G
authors.lastname: Niedermann
authors.forename: Peter
authors.initials: P
authors.lastname: van Endert
mesh_terms: 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
chemical_list: D000939:Epitopes; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D010122:Cystinyl Aminopeptidase; C105964:leucyl-cystinyl aminopeptidase; D046988:Proteasome Endopeptidase Complex