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Science 325 (5937): 213-217

Copyright © 2009 by the American Association for the Advancement of Science

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,* Gabriele Niedermann,3,* Peter van Endert1,{dagger}

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.

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.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: peter.van-endert{at}inserm.fr

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