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Published Online June 4, 2009
Science DOI: 10.1126/science.1172845

Reports

Submitted on February 27, 2009
Accepted on May 22, 2009

IRAP Identifies an Endosomal Compartment Required for MHC Class I Cross-Presentation

Loredana Saveanu 1, Oliver Carroll 1, Mirjana Weimershaus 1, Pierre Guermonprez 2, Elke Firat 3, Vivian Lindo 4, Fiona Greer 4, Jean Davoust 1, Roland Kratzer 1, Susanna R. Keller 5{dagger}, Gabriele Niedermann 3{dagger}, Peter van Endert 1*

1 INSERM, U580, 75015 Paris, France; Université Paris Descartes, Faculté de Médecine René Descartes, 75015 Paris, France.
2 INSERM, U653, 75006 Paris, France; Institut Curie, Centre de Recherche, 75006 Paris, France.
3 Clinic for Radiotherapy, University Hospital of Freiburg, 79106 Freiburg, Germany.
4 M-SCAN Ltd., Wokingham, Berkshire RG41 2TZ, UK.
5 Division of Endocrinology, Department of Internal Medicine, University of Virginia, Charlottesville, VA 22908, USA.

* To whom correspondence should be addressed.
Peter van Endert , E-mail: peter.van-endert{at}inserm.fr

{dagger}These authors contributed equally to this work.

Major histocompatibility class (MHC) 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, in a process known as cross-presentation. The cellular compartments involved in cross-presentation remain poorly defined. Here, 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 effect endogenous presentation. We propose the existence of two pathways for proteasome-dependent cross-presentation in which final peptide trimming involves IRAP in endosomes, and the related aminopeptidases in the endoplasmic reticulum.


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Science. ISSN 0036-8075 (print), 1095-9203 (online)