IRAP+ endosomes restrict TLR9 activation and signaling

Joël Babdor; Delphyne Descamps; Adiko Assi Aimé Cézaire; Mira Tohmé; Sophia Maschalidi; Irini Evnouchidou; Luiz Ricardo Vasconcellos; Mariacristina de Luca; Francois-Xavier Mauvais; Meriem Garfa-Traore; Melanie Brinkmann; Michel Chignard; Bénédicte Manoury; Loredana Saveanu

doi:10.1038/ni.3711

Journal articles

IRAP+ endosomes restrict TLR9 activation and signaling

Joël Babdor ^{1, 2, 3} Delphyne Descamps ^{1, 2, 3, 4} Adiko Assi Aimé Cézaire ^{5, 6} Mira Tohmé ^{1, 2, 3, 7} Sophia Maschalidi ^{8, 1, 2, 3} Irini Evnouchidou ^{5, 6} Luiz Ricardo Vasconcellos ^{1, 2, 9, 3} Mariacristina de Luca ^{5, 6} Francois-Xavier Mauvais ^{1, 2, 3} Meriem Garfa-Traore ^{1, 2, 3} Melanie Brinkmann ¹⁰ Michel Chignard ^{11, 2} Bénédicte Manoury ^{1, 2, 3, *} Loredana Saveanu ^{5, 6, *}

* Corresponding author

1 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades

2 USPC - Université Sorbonne Paris Cité

3 UPD5 Médecine - Université Paris Descartes - Faculté de Médecine

4 VIM - Unité de recherche Virologie et Immunologie Moléculaires

5 CRI (UMR_S_1149 / ERL_8252 / U1149) - Centre de recherche sur l'Inflammation

6 Faculté de Médecine Xavier Bichat

7 Department of Pediatrics - Division of Immunology [Boston, Massachusetts, USA]

8 IMAGINE - U1163 - Imagine - Institut des maladies génétiques

9 Laboratório de Imunoreceptores e Sinalização [Rio de Janeiro, Brazil]

10 HZI - Helmholtz Centre for Infection Research

11 CR Saint-Antoine - Centre de Recherche Saint-Antoine

Abstract : The retention of intracellular Toll-like receptors (TLRs) in the endoplasmic reticulum prevents their activation under basal conditions. TLR9 is activated by sensing ligands in specific endosomal-lysosomal compartments. Here we identified IRAP+ endosomes as major cellular compartments for the early steps of TLR9 activation in dendritic cells (DCs). Both TLR9 and its ligand, the dinucleotide CpG, were present as cargo in IRAP+ endosomes. In the absence of the aminopeptidase IRAP, the trafficking of CpG and TLR9 to lysosomes and signaling via TLR9 were enhanced in DCs and in mice following bacterial infection. IRAP stabilized CpG-containing endosomes by interacting with the actin-nucleation factor FHOD4, which slowed the trafficking of TLR9 toward lysosomes. Thus, endosomal retention of TLR9 via the interaction of IRAP with the actin cytoskeleton is a mechanism that prevents hyper-activation of TLR9 in DCs.

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Journal articles

Domain :

Life Sciences [q-bio] / Immunology

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https://www.hal.inserm.fr/inserm-01674784
Contributor : Loredana Saveanu <>
Submitted on : Wednesday, January 3, 2018 - 4:04:43 PM
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IRAP+ endosomes restrict TLR9 activation and signaling

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IRAP+ endosomes restrict TLR9 activation and signaling

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