title: PLEKHM1/DEF8/RAB7 complex regulates lysosome positioning and bone homeostasis.
abstract: Mutations of thePlekhm1gene 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 conditionalPlekhm1-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 ofPlekhm1-null osteoclasts. Thus, PLHKEM1, DEF8, FAM98A, and NDEL1 constitute a molecular complex that regulates lysosome positioning and secretion through RAB7.
authors: 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.
authors: Toshifumi
authors: T
authors: Fujiwara
authors: 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.
authors: Shiqiao
authors: S
authors: Ye
authors: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
authors: Thiago
authors: T
authors: Castro-Gomes
authors: Department of Microbiology and Immunology.
authors: Caylin G
authors: CG
authors: Winchell
authors: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
authors: Norma W
authors: NW
authors: Andrews
authors: Department of Microbiology and Immunology.
authors: Daniel E
authors: DE
authors: Voth
authors: Department of Physiology and Biophysics, and.
authors: Kottayil I
authors: KI
authors: Varughese
authors: Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors: Samuel G
authors: SG
authors: Mackintosh
authors: Department of Pathology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.
authors: Yunfeng
authors: Y
authors: Feng
authors: Center for Orthopedic Research, Dentistry and Health Sciences, The University of Western Australia, Nedlands, Western Australia, Australia.
authors: Nathan
authors: N
authors: Pavlos
authors: Department of Biochemistry & Integrative Medical Biology, School of Medicine, Keio University, Tokyo, Japan.
authors: Takashi
authors: T
authors: Nakamura
authors: 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.
authors: Stavros C
authors: SC
authors: Manolagas
authors: 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 Physiology and Biophysics, and.
authors: Haibo
authors: H
authors: Zhao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000071183:Autophagy-Related Proteins; D001862:Bone Resorption; D002454:Cell Differentiation; D002478:Cells, Cultured; D011992:Endosomes; D017353:Gene Deletion; D006706:Homeostasis; D008247:Lysosomes / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000502:physiology*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000502:physiology*; D020691:rab GTP-Binding Proteins / Q000502:physiology*; D000090802:rab7 GTP-Binding Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; C570891:Plekhm1 protein, mouse; D033921:Vesicular Transport Proteins; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C000716465:rab7 GTP-binding proteins, mouse; C000716466:rab7 GTP-binding proteins, rat; D020691:rab GTP-Binding Proteins