2. Academic Validation
  3. PLEKHM1/DEF8/RAB7 complex regulates lysosome positioning and bone homeostasis

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

  • JCI Insight. 2016 Oct 20;1(17):e86330. doi: 10.1172/jci.insight.86330.
Toshifumi Fujiwara 1,  Shiqiao Ye 1,  Thiago Castro-Gomes 2,  Caylin G Winchell 3,  Norma W Andrews 2,  Daniel E Voth 3,  Kottayil I Varughese 4,  Samuel G Mackintosh 5,  Yunfeng Feng 6,  Nathan Pavlos 7,  Takashi Nakamura 8,  Stavros C Manolagas 1,  Haibo Zhao 1 4
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
  • 3 Department of Microbiology and Immunology.
  • 4 Department of Physiology and Biophysics, and.
  • 5 Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
  • 6 Department of Pathology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.
  • 7 Center for Orthopedic Research, Dentistry and Health Sciences, The University of Western Australia, Nedlands, Western Australia, Australia.
  • 8 Department of Biochemistry & Integrative Medical Biology, School of Medicine, Keio University, Tokyo, Japan.
PMID: 27777970 DOI: 10.1172/jci.insight.86330
Abstract

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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