Leucine-Rich Repeat Kinase 1 Regulates Autophagy through Turning On TBC1D2-Dependent Rab7 Inactivation
Leucine-Rich Repeat Kinase 1 Regulates Autophagy through Turning On TBC1D2-Dependent Rab7 Inactivation
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DOI：
10.1128/mcb.00085-15
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发表时间：
2015-06
影响因子：
5.3
通讯作者：
T. Toyofuku;Keiko Morimoto;S. Sasawatari;A. Kumanogoh
中科院分区：
文献类型：
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作者：
T. Toyofuku;Keiko Morimoto;S. Sasawatari;A. Kumanogoh
摘要自噬是一个保守的过程，它使分解代谢和降解途径成为可能。Rab家族蛋白以GTP结合形式具有活性，调节自噬体的转运和融合。然而，目前还不清楚Rab激活和失活的每个循环是如何精确调节的。在这里，我们表明，富含亮氨酸的重复序列激酶1（LRRK 1）调节自噬通量控制Rab 7活性在自溶体的形成。在诱导自噬后，LRRK 1通过与VAMP 7的结合被募集到自溶小体，在那里它激活Rab 7 GTP酶激活蛋白（GAP）TBC 1D 2，从而关闭Rab 7信号传导。与该模型一致，LRRK 1缺失导致小鼠易受饥饿并破坏自溶酶体形成，如具有未降解的LC 3-II和持续高水平的Rab 7-GTP的扩大的自溶酶体的积累所证明的。这种自噬通量的缺陷部分地被具有升高的Rab 7-GAP活性的TBC 1D 2的突变形式所挽救。因此，时空调节Rab 7活性在衣霉素诱导的自噬是由LRRK 1调节。
ABSTRACT 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.