Modulation of Local PtdIns3P Levels by the PI Phosphatase MTMR3 Regulates Constitutive Autophagy
Modulation of Local PtdIns3P Levels by the PI Phosphatase MTMR3 Regulates Constitutive Autophagy
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DOI：
10.1111/j.1600-0854.2010.01034.x
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发表时间：
2010-04-01
期刊：
影响因子：
4.5
通讯作者：
Noda, Takeshi
中科院分区：
文献类型：
--
作者：
Taguchi-Atarashi, Naoko;Hamasaki, Maho;Noda, Takeshi
自噬是一种分解代谢过程，它将细胞质物质输送到溶酶体进行降解。调节自噬小体形成和大小的机制尚不清楚。在这里，我们发现自噬小体的形成是由肌管蛋白相关磷酸酶3(MTMR3)的显性负性失活突变体的过度表达所触发的。突变体MTMR3部分定位于自噬小体，PtdIns3P和两个与自噬相关的PtdIns3P结合蛋白GFP-DFCP1和GFP-WIPI-1α(WIPI49/Atg18)积累在自噬小体形成部位。MTMR3的敲除增加了自噬小体的形成，而野生型MTMR3的过表达导致新生自噬小体明显变小，自噬活性净减少。这些结果表明，自噬的启动依赖于PI 3-激酶和PI 3-磷酸酶活性之间的平衡。自噬小体形成部位的局部PtdIns3P水平决定了自噬的启动和自噬体膜结构的大小。
Autophagy is a catabolic process that delivers cytoplasmic material to the lysosome for degradation. The mechanisms regulating autophagosome formation and size remain unclear. Here, we show that autophagosome formation was triggered by the overexpression of a dominant-negative inactive mutant of Myotubularin-related phosphatase 3 (MTMR3). Mutant MTMR3 partially localized to autophagosomes, and PtdIns3P and two autophagy-related PtdIns3P-binding proteins, GFP-DFCP1 and GFP-WIPI-1 alpha (WIPI49/Atg18), accumulated at sites of autophagosome formation. Knock-down of MTMR3 increased autophagosome formation, and overexpression of wild-type MTMR3 led to significantly smaller nascent autophagosomes and a net reduction in autophagic activity. These results indicate that autophagy initiation depends on the balance between PI 3-kinase and PI 3-phosphatase activity. Local levels of PtdIns3P at the site of autophagosome formation determine autophagy initiation and the size of the autophagosome membrane structure.