INSERM U932 Immunité et Cancer, Institut Curie, Paris Sciences & Lettres Research University, F-75248 Paris, Cedex 05, France.
Institut Curie, Paris Sciences & Lettres Research University, CNRS, UMR 144, F-75005 Paris, France.
Sci Immunol. 2017 Oct 27;2(16). doi: 10.1126/sciimmunol.aak9573.
Dendritic cells (DCs) patrol their environment by linking antigen acquisition by macropinocytosis to cell locomotion. DC activation upon bacterial sensing inhibits macropinocytosis and increases DC migration, thus promoting the arrival of DCs to lymph nodes for antigen presentation to T cells. The signaling events that trigger such changes are not fully understood. We show that lysosome signaling plays a critical role in this process. Upon bacterial sensing, lysosomal calcium is released by the ionic channel TRPML1 (transient receptor potential cation channel, mucolipin subfamily, member 1), which activates the actin-based motor protein myosin II at the cell rear, promoting fast and directional migration. Lysosomal calcium further induces the activation of the transcription factor EB (TFEB), which translocates to the nucleus to maintain TRPML1 expression. We found that the TRPML1-TFEB axis results from the down-regulation of macropinocytosis after bacterial sensing by DCs. Lysosomal signaling therefore emerges as a hitherto unexpected link between macropinocytosis, actomyosin cytoskeleton organization, and DC migration.
树突状细胞 (DCs) 通过将巨胞饮作用与细胞运动相结合来巡视其环境。在细菌感应时，DC 的激活会抑制巨胞饮作用并增加 DC 迁移，从而促进 DC 到达淋巴结以将抗原呈递给 T 细胞。触发这些变化的信号事件尚未完全了解。我们表明溶酶体信号在这个过程中起着关键作用。在细菌感应时，离子通道 TRPML1（瞬时受体电位阳离子通道，粘蛋白亚家族，成员 1）释放溶酶体钙，这激活了细胞后部的肌球蛋白 II 基于肌动蛋白的运动蛋白，促进快速和定向迁移。溶酶体钙进一步诱导转录因子 EB（TFEB）的激活，TFEB 易位到细胞核以维持 TRPML1 的表达。我们发现，TRPML1-TFEB 轴是 DC 感应细菌后巨胞饮作用下调的结果。因此，溶酶体信号作为巨胞饮作用、肌动球蛋白细胞骨架组织和 DC 迁移之间的一个前所未有的联系而出现。
