PLEKHM1/DEF8/RAB7 complex regulates lysosome positioning and bone homeostasis
PLEKHM1/DEF8/RAB7 complex regulates lysosome positioning and bone homeostasis
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DOI：
10.1172/jci.insight.86330
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发表时间：
2016-10-20
期刊：
影响因子：
8
通讯作者：
Zhao, Haibo
中科院分区：
文献类型：
--
作者：
Fujiwara, Toshifumi;Ye, Shiqiao;Zhao, Haibo
人类和大鼠中 Plekhm1 基因的突变会导致石骨症，这是一种遗传性骨病，其特征是破骨细胞骨吸收减少。 PLEKHM1 与 RAB7 结合，对于溶酶体运输至关重要。然而，PLEKHM1 调节溶酶体途径的分子机制仍不清楚。在这里，我们生成了种系和条件性 Plekhm1 缺陷小鼠。除了骨小梁质量增加外，这些小鼠的主要器官没有表现出明显的异常。此外，PLEKHM1 的缺失消除了溶酶体的外周分布和破骨细胞中的骨吸收。从机制上讲，我们表明 DEF8 与 PLEKHM1 相互作用并促进其与 RAB7 的结合，而 FAM98A 和 NDEL1 与 PLEKHM1 的结合将溶酶体连接到微管。重要的是，抑制这些蛋白质会导致溶酶体定位和骨吸收缺陷，类似于 Plekhm1 缺失的破骨细胞。因此，PLHKEM1、DEF8、FAM98A和NDEL1构成了通过RAB7调节溶酶体定位和分泌的分子复合物。
Mutations of the Plekhm1 gene in humans and rats cause osteopetrosis, an inherited bone disease characterized by diminished bone resorption by osteoclasts. PLEKHM1 binds to RAB7 and is critical for lysosome trafficking. However, the molecular mechanisms by which PLEKHM1 regulates lysosomal pathways remain unknown. Here, we generated germline and conditional Plekhm1deficient mice. These mice displayed no overt abnormalities in major organs, except for an increase in trabecular bone mass. Furthermore, loss of PLEKHM1 abrogated the peripheral distribution of lysosomes and bone resorption in osteoclasts. Mechanistically, we indicated that DEF8 interacts with PLEKHM1 and promotes its binding to RAB7, whereas the binding of FAM98A and NDEL1 with PLEKHM1 connects lysosomes to microtubules. Importantly, suppression of these proteins results in lysosome positioning and bone resorption defects similar to those of Plekhm1-null osteoclasts. Thus, PLHKEM1, DEF8, FAM98A, and NDEL1 constitute a molecular complex that regulates lysosome positioning and secretion through RAB7.