Rubicon and PLEKHM1 negatively regulate the endocytic/autophagic pathway via a novel Rab7-binding domain.
Rubicon and PLEKHM1 negatively regulate the endocytic/autophagic pathway via a novel Rab7-binding domain.
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DOI：
10.1091/mbc.e10-06-0495
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发表时间：
2010-12
影响因子：
3.3
通讯作者：
Yoshimori T
中科院分区：
文献类型：
--
作者：
Tabata K;Matsunaga K;Sakane A;Sasaki T;Noda T;Yoshimori T
Rubicon是Beclin 1-PI 3-激酶复合物及其同源物PLEKHM 1的亚基，通过与Rab 7的相互作用负调控内吞途径。与Beclin 1-PI 3-激酶复合物和Rab 7的同步缔合对于Rubicon的功能是必需的，而不是PLEKHM 1。内吞和自噬途径参与外源性和内源性物质向溶酶体的膜运输。然而，调节这些途径的机制在很大程度上是未知的。我们以前报道，Rubicon，Beclin 1结合蛋白，负调控自噬和内吞途径的不明机制。在这项研究中，我们进行了数据库搜索，以确定潜在的Rubicon同源物，共享共同的C-末端结构域，称为RH域。其中之一，PLEKHM 1，骨硬化症的致病基因，也抑制内吞转运，但不自噬体成熟。Rubicon和PLEKHM 1通过其RH结构域特异性地直接与Rab 7相互作用，这种相互作用对其功能至关重要。此外，我们表明，Rubicon，而不是PLEKHM 1独特的调节膜运输通过同时结合Rab 7和PI 3-激酶。
Rubicon, a subunit of the Beclin 1-PI3-kinase complex and its homologue, PLEKHM1, negatively regulate endocytic pathway through the interaction with Rab7. Synchronous association with the Beclin 1–PI3-kinase complex and Rab7 is necessary for the function of Rubicon, but not PLEKHM1. The endocytic and autophagic pathways are involved in the membrane trafficking of exogenous and endogenous materials to lysosomes. However, the mechanisms that regulate these pathways are largely unknown. We previously reported that Rubicon, a Beclin 1–binding protein, negatively regulates both the autophagic and endocytic pathways by unidentified mechanisms. In this study, we performed database searches to identify potential Rubicon homologues that share the common C-terminal domain, termed the RH domain. One of them, PLEKHM1, the causative gene of osteopetrosis, also suppresses endocytic transport but not autophagosome maturation. Rubicon and PLEKHM1 specifically and directly interact with Rab7 via their RH domain, and this interaction is critical for their function. Furthermore, we show that Rubicon but not PLEKHM1 uniquely regulates membrane trafficking via simultaneously binding both Rab7 and PI3-kinase.