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首页> 外文期刊>Molecular and Cellular Biology >Leucine-Rich Repeat Kinase 1 Regulates Autophagy through Turning On TBC1D2-Dependent Rab7 Inactivation
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Leucine-Rich Repeat Kinase 1 Regulates Autophagy through Turning On TBC1D2-Dependent Rab7 Inactivation

机译：富含亮氨酸的重复激酶1通过开启TBC1D2依赖性Rab7失活调节自噬。

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Autophagy is a conserved process that enables catabolic and degradative pathways. Rab family proteins, which are active in the GTP-bound form, regulate the transport and fusion of autophagosomes. However, it remains unclear how each cycle of Rab activation and inactivation is precisely regulated. Here, we show that leucine-rich repeat kinase 1 (LRRK1) regulates autophagic flux by controlling Rab7 activity in autolysosome formation. Upon induction of autophagy, LRRK1 was recruited via an association with VAMP7 to the autolysosome, where it activated the Rab7 GTPase-activating protein (GAP) TBC1D2, thereby switching off Rab7 signaling. Consistent with this model, LRRK1 deletion caused mice to be vulnerable to starvation and disrupted autolysosome formation, as evidenced by the accumulation of enlarged autolysosomes with undegraded LC3-II and persistently high levels of Rab7-GTP. This defect in autophagic flux was partially rescued by a mutant form of TBC1D2 with elevated Rab7-GAP activity. Thus, the spatiotemporal regulation of Rab7 activity during tunicamycin-induced autophagy is regulated by LRRK1.
机译：自噬是一个保守的过程，可以实现分解代谢和降解途径。 Rab家族蛋白以GTP结合形式活跃，调节自噬体的运输和融合。然而，还不清楚如何精确调节Rab激活和失活的每个循环。在这里，我们显示，富含亮氨酸的重复激酶1（LRRK1）通过控制溶酶体形成中的Rab7活性来调节自噬通量。自噬诱导后，LRRK1通过与VAMP7的结合募集到自溶酶体中，在那里它激活了Rab7 GTPase激活蛋白（GAP）TBC1D2，从而关闭了Rab7信号传导。与该模型一致，LRRK1缺失导致小鼠容易饿死并破坏了溶酶体的形成，这是由未降解的LC3-II和持续高水平的Rab7-GTP积累的扩大的溶酶体的积累所证明的。自噬通量的这种缺陷可通过具有提高的Rab7-GAP活性的TBC1D2突变形式来部分挽救。因此，LRRK1调节衣霉素诱导的自噬过程中Rab7活性的时空调节。

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