PLEKHM1/DEF8/RAB7 complex regulates lysosome positioning and bone homeostasis.


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 Plekhm1-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 Plekhm1-null osteoclasts. Thus, PLHKEM1, DEF8, FAM98A, and NDEL1 constitute a molecular complex that regulates lysosome positioning and secretion through RAB7.

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@article{Fujiwara2016PLEKHM1DEF8RAB7CR, title={PLEKHM1/DEF8/RAB7 complex regulates lysosome positioning and bone homeostasis.}, author={Toshifumi Fujiwara and Shiqiao Ye and Thiago Castro-Gomes and Caylin G. Winchell and Norma Windsor Andrews and Daniel E. Voth and Kottayil Iype Varughese and Samuel G. Mackintosh and Yunfeng Feng and Nathan Pavlos and Takashi Nakamura and Stavros C Manolagas and Haibo Zhao}, journal={JCI insight}, year={2016}, volume={1 17}, pages={e86330} }