Center for Osteoporosis and Metabolic Bone Diseases, Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
JCI Insight. 2016 Oct 20;1(17):e86330. doi: 10.1172/jci.insight.86330.
Mutations of the 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 -deficient 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 -null osteoclasts. Thus, PLHKEM1, DEF8, FAM98A, and NDEL1 constitute a molecular complex that regulates lysosome positioning and secretion through RAB7.
人类和大鼠基因的突变导致成骨不全症，这是一种遗传性骨病，其特征是破骨细胞的骨吸收减少。PLEKHM1 与 RAB7 结合，对溶酶体运输至关重要。然而，PLEKHM1 调节溶酶体途径的分子机制尚不清楚。在这里，我们生成了种系和条件性 -缺陷小鼠。这些小鼠除了小梁骨量增加外，主要器官没有明显异常。此外，PLEKHM1 的缺失消除了破骨细胞中溶酶体的外周分布和骨吸收。在机制上，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上。重要的是，这些蛋白质的抑制导致溶酶体定位和骨吸收缺陷类似于 -缺陷破骨细胞。因此，PLEKHM1、DEF8、FAM98A 和 NDEL1 构成一个分子复合物，通过 RAB7 调节溶酶体定位和分泌。
