Institut National de la Santé et de la Recherché Médicale, Unité 1151, Paris, France.
Centre National de la Recherche Scientifique, Unité 8253, Paris, France.
Nat Immunol. 2017 May;18(5):509-518. doi: 10.1038/ni.3711. Epub 2017 Mar 20.
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.
细胞内 Toll 样受体 (TLR) 在粗面内质网中的保留可防止其在基础条件下被激活。TLR9 通过在特定的内体溶酶体隔室中检测配体而被激活。在这里，我们确定了 IRAP 内体作为树突状细胞 (DC) 中 TLR9 激活早期步骤的主要细胞隔室。TLR9 和其配体，二核苷酸 CpG，都作为货物存在于 IRAP 内体中。在缺乏氨肽酶 IRAP 的情况下，CpG 和 TLR9 向溶酶体的运输以及细菌感染后 DC 中的 TLR9 信号转导增强。IRAP 通过与肌动蛋白成核因子 FHOD4 相互作用稳定含 CpG 的内体，从而减缓 TLR9 向溶酶体的运输。因此，IRAP 通过与肌动蛋白细胞骨架相互作用对内体 TLR9 的保留是防止 TLR9 在 DC 中过度激活的一种机制。
