PMEPA1 and NEDD4 control the proton production of osteoclasts by regulating vesicular trafficking.
Animals
Autophagy
Binding Sites
Bone Resorption
/ metabolism
Cells, Cultured
Membrane Proteins
/ chemistry
Mice
Mice, Inbred C57BL
Mutation
Nedd4 Ubiquitin Protein Ligases
/ metabolism
Osteoclasts
/ metabolism
Protein Binding
Protein Transport
Protons
Transport Vesicles
/ metabolism
Vacuolar Proton-Translocating ATPases
/ metabolism
NEDD4
V-ATPase
lysosomal secretion
osteoclast
proton production
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
22
07
2020
revised:
13
11
2020
accepted:
01
12
2020
entrez:
23
1
2021
pubmed:
24
1
2021
medline:
29
6
2021
Statut:
ppublish
Résumé
Osteoclast bone resorption activity is critically regulated to maintain bone homeostasis. Osteoclasts resorb bone by producing protons and acid hydrolase via lysosomal secretion, however, a detailed mechanism remains elusive. PMEPA1 is a vesicular membrane protein, which binds to the NEDD4 family member of ubiquitin ligases. We have previously reported that Pmepa1 is highly expressed in bone resorbing osteoclasts, and regulates bone resorption. Here, we investigated the mechanism of bone resorption regulated by PMEPA1. Mutant mice lacking NEDD4-binding domains of PMEPA1 displayed enhanced bone volume, and reduced bone resorption activity in comparison with those of WT mice. Analysis with pH-sensitive fluorescence probe revealed that proton secretion from osteoclasts significantly decreased in Pmepa1 mutant osteoclasts. Immunofluorescence analysis revealed that PMEPA1 was colocalized with NEDD4, V0A3, and V0D2 subunits of vacuolar ATPase, which regulate the proton production of osteoclasts. In addition, Nedd4 knockdown reduced bone resorption and proton secretion of osteoclasts. Furthermore, Pmepa1 mutation and Nedd4 knockdown altered the cytoplasmic distribution of components of V-ATPase and expression of autophagy-related proteins, suggesting that lysosomal secretion is affected. Collectively, these findings indicate that PMEPA1 controls proton secretion from osteoclasts via NEDD4 by regulating vesicular trafficking, and NEDD4 is an important regulator of bone resorption.
Identifiants
pubmed: 33484199
doi: 10.1096/fj.202001795R
doi:
Substances chimiques
Membrane Proteins
0
Pmepa1 protein, mouse
0
Protons
0
Nedd4 Ubiquitin Protein Ligases
EC 2.3.2.26
Nedd4 protein, mouse
EC 2.3.2.26
Vacuolar Proton-Translocating ATPases
EC 3.6.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e21281Informations de copyright
© 2021 Federation of American Societies for Experimental Biology.
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