Transcriptional activation of lysosomal exocytosis promotes cellular clearance.
Transcriptional activation of lysosomal exocytosis promotes cellular clearance.
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DOI：
10.1016/j.devcel.2011.07.016
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发表时间：
2011-09-13
影响因子：
11.8
通讯作者：
Ballabio, Andrea
中科院分区：
文献类型：
--
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
溶酶体是主要参与降解和再循环过程的细胞器。在溶酶体胞吐（一种Ca2+调节的过程）期间，溶酶体停靠在细胞表面并与质膜（PM）融合，将其内容物排空到细胞外。这个过程在分泌和PM修复中起重要作用。在这里，我们表明，转录因子EB（TFEB）调节溶酶体胞吐。TFEB通过激活溶酶体Ca2+通道MCOLN1提高细胞内Ca2+水平，增加PM附近的溶酶体池，并促进其与PM融合。TFEB过表达诱导的溶酶体胞吐作用在体外和体内溶酶体贮积病（LSD）中挽救了病理性贮积并恢复了正常的细胞形态。我们的数据表明，溶酶体胞吐作用可能直接调节细胞清除，并提出了一种替代的治疗策略与细胞内储存的疾病。TFEB调节的转录诱导溶酶体与质膜（PM）对接。TFEB通过MCOLN 1提高Ca2+水平促进溶酶体与PM融合。TFEB因此可以挽救溶酶体贮积病（LSD）细胞中的病理性贮积。体内TFEB基因递送挽救LSD小鼠中的贮积、炎症和凋亡。
Lysosomes are cellular organelles primarily involved in degradation and recycling processes. During lysosomal exocytosis, a Ca2+-regulated process, lysosomes are docked to the cell surface and fuse with the plasma membrane (PM), emptying their content outside the cell. This process has an important role in secretion and PM repair. Here we show that the transcription factor EB (TFEB) regulates lysosomal exocytosis. TFEB increases the pool of lysosomes in the proximity of the PM and promotes their fusion with PM by raising intracellular Ca2+ levels through the activation of the lysosomal Ca2+ channel MCOLN1. Induction of lysosomal exocytosis by TFEB overexpression rescued pathologic storage and restored normal cellular morphology both in vitro and in vivo in lysosomal storage diseases (LSDs). Our data indicate that lysosomal exocytosis may directly modulate cellular clearance and suggest an alternative therapeutic strategy for disorders associated with intracellular storage. ► TFEB-regulated transcription induces lysosomal docking to the plasma membrane (PM) ► TFEB promotes lysosomal fusion with the PM by raising Ca2+ levels through MCOLN1 ► TFEB can thus rescue pathological storage in lysosomal storage disease (LSD) cells ► In vivo TFEB gene delivery rescues storage, inflammation, and apoptosis in LSD mice
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影响因子：
11.4
作者：
Fraldi, Alessandro;Annunziata, Fabio;Ballabio, Andrea
通讯作者：
Ballabio, Andrea
影响因子：
7.7
作者：
Andrews, NW
通讯作者：
Andrews, NW
影响因子：
3
作者：
Carmen Louzao, M.;Espina, Begona;Botana, Luis M.
通讯作者：
Botana, Luis M.
膜近端溶酶体是负责非分泌细胞中钙依赖性胞吐作用的主要囊泡。
影响因子：
7.8
作者：
Jaiswal, Jyoti K;Andrews, Norma W;Simon, Sanford M
通讯作者：
Simon, Sanford M
影响因子：
3.8
作者：
LaPlante, Janice M.;Sun, Mei;Vassilev, Peter M.
通讯作者：
Vassilev, Peter M.