A TRP channel in the lysosome regulates large particle phagocytosis via focal exocytosis.
A TRP channel in the lysosome regulates large particle phagocytosis via focal exocytosis.
复制标题
DOI：
10.1016/j.devcel.2013.08.003
复制
发表时间：
2013-09-16
影响因子：
11.8
通讯作者：
Xu, Haoxing
中科院分区：
文献类型：
--
作者：
Samie, Mohammad;Wang, Xiang;Zhang, Xiaoli;Goschka, Andrew;Li, Xinran;Cheng, Xiping;Gregg, Evan;Azar, Marlene;Zhuo, Yue;Garrity, Abigail G.;Gao, Qiong;Slaugenhaupt, Susan;Pickel, Jim;Zolov, Sergey N.;Weisman, Lois S.;Lenk, Guy M.;Titus, Steve;Bryant-Genevier, Marthe;Southall, Noel;Juan, Marugan;Ferrer, Marc;Xu, Haoxing
大细胞外颗粒（例如凋亡小体）的吞噬作用需要传递细胞内内体和溶酶体膜以形成质膜伪足。在这里，我们确定粘脂蛋白 TRP 通道 1 (TRPML1) 是调节局灶性胞吐作用和吞噬体生物发生的关键溶酶体 Ca2+ 通道。颗粒摄取和溶酶体胞吐作用均受到合成 TRPML1 阻滞剂的抑制，并且在从 TRPML1 敲除小鼠中分离的巨噬细胞中存在缺陷。此外，TRPML1 过表达和 TRPML1 激动剂促进溶酶体胞吐作用和颗粒摄取。使用延时共聚焦成像和直接膜片钳吞噬体膜，我们发现颗粒结合诱导溶酶体 PI(3,5)P2 升高，从而触发 TRPML1 介导的溶酶体 Ca2+ 释放，特别是在摄取部位，通过溶酶体胞吐作用快速将 TRPML1 驻留的溶酶体膜传递到新生的吞噬体。因此，大颗粒的吞噬摄入会激活磷酸肌醇和 Ca2+ 依赖性胞吐途径，为伪足延伸提供必要的膜，从而清除体内衰老和凋亡细胞。
Phagocytosis of large extracellular particles such as apoptotic bodies requires delivery of the intracellular endosomal and lysosomal membranes to form plasmalemmal pseudopods. Here we identified Mucolipin TRP channel 1 (TRPML1) as the key lysosomal Ca2+ channel regulating focal exocytosis and phagosome biogenesis. Both particle ingestion and lysosomal exocytosis are inhibited by synthetic TRPML1 blockers, and are defective in macrophages isolated from TRPML1 knockout mice. Furthermore, TRPML1 overexpression and TRPML1 agonists facilitate both lysosomal exocytosis and particle uptake. Using time-lapse confocal imaging and direct patch-clamping of phagosomal membranes, we found that particle binding induces lysosomal PI(3,5)P2 elevation to trigger TRPML1-mediated lysosomal Ca2+ release specifically at the site of uptake, rapidly delivering TRPML1-resident lysosomal membranes to nascent phagosomes via lysosomal exocytosis. Thus phagocytic ingestion of large particles activates a phosphoinositide- and Ca2+- dependent exocytosis pathway to provide membranes necessary for pseudopod extension, leading to clearance of senescent and apoptotic cells in vivo.
登录
查看更多内容
影响因子：
16.6
作者：
Dong, Xian-ping;Shen, Dongbiao;Wang, Xiang;Dawson, Taylor;Li, Xinran;Zhang, Qi;Cheng, Xiping;Zhang, Yanling;Weisman, Lois S.;Delling, Markus;Xu, Haoxing
通讯作者：
Xu, Haoxing
影响因子：
11.8
作者：
Macia, Eric;Ehrlich, Marcelo;Kirchhausen, Tomas
通讯作者：
Kirchhausen, Tomas
影响因子：
11.8
作者：
Medina, Diego L.;Fraldi, Alessandro;Bouche, Valentina;Annunziata, Fabio;Mansueto, Gelsomina;Spampanato, Carmine;Puri, Claudia;Pignata, Antonella;Martina, Jose A.;Sardiello, Marco;Palmieri, Michela;Polishchuk, Roman;Puertollano, Rosa;Ballabio, Andrea
通讯作者：
Ballabio, Andrea
DOI：
10.1083/jcb.200605004
发表时间：
2006-09-25
期刊：
The Journal of cell biology
影响因子：
--
作者：
Czibener C;Sherer NM;Becker SM;Pypaert M;Hui E;Chapman ER;Mothes W;Andrews NW
通讯作者：
Andrews NW
影响因子：
3.5
作者：
Ferguson, Cole J.;Lenk, Guy M.;Meisler, Miriam H.
通讯作者：
Meisler, Miriam H.