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

Toshifumi Fujiwara, Shiqiao Ye, Thiago Castro-Gomes, Caylin G. Winchell, Norma W. Andrews, Daniel E. Voth, Kottayil I. Varughese, Samuel G. Mackintosh, Yunfeng Feng, Nathan Pavlos, Takashi Nakamura, Stavros C. Manolagas, Haibo Zhao

Research output: Contribution to journalArticle

15 Citations (Scopus)

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 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.

Original languageEnglish
Article numbere86330
JournalJCI Insight
Volume1
Issue number17
DOIs
Publication statusPublished - Jan 1 2016

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Lysosomes
Homeostasis
Bone and Bones
Osteoclasts
Bone Resorption
Osteopetrosis
Bone Diseases
Microtubules
Mutation
Genes
Proteins

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Fujiwara, T., Ye, S., Castro-Gomes, T., Winchell, C. G., Andrews, N. W., Voth, D. E., ... Zhao, H. (2016). PLEKHM1/DEF8/RAB7 complex regulates lysosome positioning and bone homeostasis. JCI Insight, 1(17), [e86330]. https://doi.org/10.1172/jci.insight.86330

PLEKHM1/DEF8/RAB7 complex regulates lysosome positioning and bone homeostasis. / Fujiwara, Toshifumi; Ye, Shiqiao; Castro-Gomes, Thiago; Winchell, Caylin G.; Andrews, Norma W.; Voth, Daniel E.; Varughese, Kottayil I.; Mackintosh, Samuel G.; Feng, Yunfeng; Pavlos, Nathan; Nakamura, Takashi; Manolagas, Stavros C.; Zhao, Haibo.

In: JCI Insight, Vol. 1, No. 17, e86330, 01.01.2016.

Research output: Contribution to journalArticle

Fujiwara, T, Ye, S, Castro-Gomes, T, Winchell, CG, Andrews, NW, Voth, DE, Varughese, KI, Mackintosh, SG, Feng, Y, Pavlos, N, Nakamura, T, Manolagas, SC & Zhao, H 2016, 'PLEKHM1/DEF8/RAB7 complex regulates lysosome positioning and bone homeostasis', JCI Insight, vol. 1, no. 17, e86330. https://doi.org/10.1172/jci.insight.86330
Fujiwara T, Ye S, Castro-Gomes T, Winchell CG, Andrews NW, Voth DE et al. PLEKHM1/DEF8/RAB7 complex regulates lysosome positioning and bone homeostasis. JCI Insight. 2016 Jan 1;1(17). e86330. https://doi.org/10.1172/jci.insight.86330
Fujiwara, Toshifumi ; Ye, Shiqiao ; Castro-Gomes, Thiago ; Winchell, Caylin G. ; Andrews, Norma W. ; Voth, Daniel E. ; Varughese, Kottayil I. ; Mackintosh, Samuel G. ; Feng, Yunfeng ; Pavlos, Nathan ; Nakamura, Takashi ; Manolagas, Stavros C. ; Zhao, Haibo. / PLEKHM1/DEF8/RAB7 complex regulates lysosome positioning and bone homeostasis. In: JCI Insight. 2016 ; Vol. 1, No. 17.
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