Phosphatidylinositol 4,5-bisphosphate controls Rab7 and PLEKHM1 membrane cycling during autophagosome-lysosome fusion.,The EMBO Journal

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Phosphatidylinositol 4,5-bisphosphate controls Rab7 and PLEKHM1 membrane cycling during autophagosome-lysosome fusion.
The EMBO Journal ( IF 9.4 ) Pub Date : 2019-03-13 , DOI: 10.15252/embj.2018100312
Takashi Baba ₁ , Daniel J Toth ₁ , Nivedita Sengupta ₁ , Yeun Ju Kim ₁ , Tamas Balla ₁

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The small GTPase Rab7 is a key organizer of receptor sorting and lysosomal degradation by recruiting of a variety of effectors depending on its GDP/GTP-bound state. However, molecular mechanisms that trigger Rab7 inactivation remain elusive. Here we find that, among the endosomal pools, Rab7-positive compartments possess the highest level of PI4P, which is primarily produced by PI4K2A kinase. Acute conversion of this endosomal PI4P to PI(4,5)P2 causes Rab7 dissociation from late endosomes and releases a regulator of autophagosome-lysosome fusion, PLEKHM1, from the membrane. Rab7 effectors Vps35 and RILP are not affected by acute PI(4,5)P2 production. Deletion of PI4K2A greatly reduces PIP5Kγ-mediated PI(4,5)P2 production in Rab7-positive endosomes leading to impaired Rab7 inactivation and increased number of LC3-positive structures with defective autophagosome-lysosome fusion. These results reveal a late endosomal PI4P-PI(4,5)P2 -dependent regulatory loop that impacts autophagosome flux by affecting Rab7 cycling and PLEKHM1 association.

中文翻译：

磷脂酰肌醇 4,5-二磷酸在自噬体-溶酶体融合过程中控制 Rab7 和 PLEKHM1 膜循环。

小 GTP 酶 Rab7 是受体分选和溶酶体降解的关键组织者，根据其 GDP/GTP 结合状态招募各种效应子。然而，触发 Rab7 失活的分子机制仍然难以捉摸。在这里，我们发现，在内体库中，Rab7 阳性区室具有最高水平的 PI4P，其主要由 PI4K2A 激酶产生。这种内体 PI4P 急性转化为 PI(4,5)P2 导致 Rab7 从晚期内体解离，并从膜上释放自噬体-溶酶体融合的调节因子 PLEKHM1。 Rab7 效应器 Vps35 和 RILP 不受急性 PI(4,5)P2 产生的影响。 PI4K2A 的缺失极大地减少了 Rab7 阳性核内体中 PIP5Kγ 介导的 PI(4,5)P2 的产生，导致 Rab7 失活受损，并且自噬体-溶酶体融合缺陷的 LC3 阳性结构数量增加。这些结果揭示了晚期内体 PI4P-PI(4,5)P2 依赖性调节环路，通过影响 Rab7 循环和 PLEKHM1 关联来影响自噬体通量。

更新日期：2019-04-15

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