IRAP+ endosomes restrict TLR9 activation and signaling

被引：36

作者：

Babdor, Joel ^{[1
,2
,3
]}

Descamps, Delphyne ^{[1
,2
,3
,4
]}

Adiko, Aime Cezaire ^{[5
,6
]}

Tohme, Mira ^{[1
,2
,3
,7
]}

Maschalidi, Sophia ^{[1
,2
,3
,8
]}

Evnouchidou, Irini ^{[5
,6
]}

Vasconcellos, Luiz Ricardo ^{[1
,2
,3
,9
]}

De Luca, Mariacristina ^{[5
,6
]}

Mauvais, Francois-Xavier ^{[1
,2
,3
]}

Garfa-Traore, Meriem ^{[1
,2
,3
]}

Brinkmann, Melanie M. ^{[10
]}

Chignard, Michel ^{[11
,12
]}

Manoury, Benedicte ^{[1
,2
,3
]}

Saveanu, Loredana ^{[5
,6
]}

机构：

[1] INSERM, Unite 1151, Paris, France

[2] CNRS, Unite 8253, Paris, France

[3] Univ Paris 05, Sorbonne Paris Cite, Fac Med Paris Descartes, Paris, France

[4] Univ Paris Saclay, INRA, VIM, Jouy En Josas, France

[5] Ctr Rech Inflammat, Unite UMR 1149, INSERM, Paris, France

[6] Univ Paris Diderot, Fac Med Xavier Bichat, Paris, France

[7] Harvard Med Sch, Dept Pediat, Boston Childrens Hosp, Div Immunol, Boston, MA USA

[8] INSERM, UMR1163, Lab Normal & Pathol Homeostasis Immune Syst, Paris, France

[9] Univ Fed Rio de Janeiro, Inst Microbiologia Paulo de Goes, Lab Inflamacao & Imunidade, Rio De Janeiro, Brazil

[10] Helmholtz Ctr Infect Res, Braunschweig, Germany

[11] CDR St Antoine, UMR S 938, INSERM, Paris, France

[12] UPMC Univ Paris 06, CDR St Antoine, UMR S 938, Sorbonne Univ, Paris, France

来源：

NATURE IMMUNOLOGY | 2017年 / 18卷 / 05期

关键词：

RECEPTOR; 9; CROSS-PRESENTATION; DENDRITIC CELLS; TRAFFICKING; PROTEIN; COMPARTMENT; CLEAVAGE; FORMINS; ALPHA; DNA;

D O I：

10.1038/ni.3711

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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.

引用

页码：509 / 518

页数：10

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