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IRAP+ endosomes restrict TLR9 activation and signaling.
Babdor, Joel Descamps, Delphyne Adiko, Aimé Cézaire Tohmé, Mira Maschalidi, Sophia Evnouchidou, Irini Vasconcellos, Luiz Ricardo De Luca, Mariacristina Mauvais, Francois-Xavier Garfa-Traore, Meriem
Babdor, Joel
Descamps, Delphyne
Adiko, Aimé Cézaire
Tohmé, Mira
Maschalidi, Sophia
Evnouchidou, Irini
Vasconcellos, Luiz Ricardo
De Luca, Mariacristina
Mauvais, Francois-Xavier
Garfa-Traore, Meriem
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2017-05
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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.
Citation
IRAP+ endosomes restrict TLR9 activation and signaling. 2017, 18 (5):509-518 Nat. Immunol.
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en
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1529-2916