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Cell surface-bound La protein regulates the cell fusion stage of osteoclastogenesis

Multinucleated osteoclasts, essential for skeletal remodeling in health and disease, are formed by the fusion of osteoclast precursors, where each fusion event raises their bone-resorbing activity. Here we show that the nuclear RNA chaperone, La protein has an additional function as an osteoclast fu...

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Autores principales: Whitlock, Jarred M., Leikina, Evgenia, Melikov, Kamran, De Castro, Luis Fernandez, Mattijssen, Sandy, Maraia, Richard J., Collins, Michael T., Chernomordik, Leonid V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9899215/
https://www.ncbi.nlm.nih.gov/pubmed/36739273
http://dx.doi.org/10.1038/s41467-023-36168-x
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author Whitlock, Jarred M.
Leikina, Evgenia
Melikov, Kamran
De Castro, Luis Fernandez
Mattijssen, Sandy
Maraia, Richard J.
Collins, Michael T.
Chernomordik, Leonid V.
author_facet Whitlock, Jarred M.
Leikina, Evgenia
Melikov, Kamran
De Castro, Luis Fernandez
Mattijssen, Sandy
Maraia, Richard J.
Collins, Michael T.
Chernomordik, Leonid V.
author_sort Whitlock, Jarred M.
collection PubMed
description Multinucleated osteoclasts, essential for skeletal remodeling in health and disease, are formed by the fusion of osteoclast precursors, where each fusion event raises their bone-resorbing activity. Here we show that the nuclear RNA chaperone, La protein has an additional function as an osteoclast fusion regulator. Monocyte-to-osteoclast differentiation starts with a drastic decrease in La levels. As fusion begins, La reappears as a low molecular weight species at the osteoclast surface, where it promotes fusion. La’s role in promoting osteoclast fusion is independent of canonical La-RNA interactions and involves direct interactions between La and Annexin A5, which anchors La to transiently exposed phosphatidylserine at the surface of fusing osteoclasts. Disappearance of cell-surface La, and the return of full length La to the nuclei of mature, multinucleated osteoclasts, acts as an off switch of their fusion activity. Targeting surface La in a novel explant model of fibrous dysplasia inhibits excessive osteoclast formation characteristic of this disease, highlighting La’s potential as a therapeutic target.
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spelling pubmed-98992152023-02-06 Cell surface-bound La protein regulates the cell fusion stage of osteoclastogenesis Whitlock, Jarred M. Leikina, Evgenia Melikov, Kamran De Castro, Luis Fernandez Mattijssen, Sandy Maraia, Richard J. Collins, Michael T. Chernomordik, Leonid V. Nat Commun Article Multinucleated osteoclasts, essential for skeletal remodeling in health and disease, are formed by the fusion of osteoclast precursors, where each fusion event raises their bone-resorbing activity. Here we show that the nuclear RNA chaperone, La protein has an additional function as an osteoclast fusion regulator. Monocyte-to-osteoclast differentiation starts with a drastic decrease in La levels. As fusion begins, La reappears as a low molecular weight species at the osteoclast surface, where it promotes fusion. La’s role in promoting osteoclast fusion is independent of canonical La-RNA interactions and involves direct interactions between La and Annexin A5, which anchors La to transiently exposed phosphatidylserine at the surface of fusing osteoclasts. Disappearance of cell-surface La, and the return of full length La to the nuclei of mature, multinucleated osteoclasts, acts as an off switch of their fusion activity. Targeting surface La in a novel explant model of fibrous dysplasia inhibits excessive osteoclast formation characteristic of this disease, highlighting La’s potential as a therapeutic target. Nature Publishing Group UK 2023-02-04 /pmc/articles/PMC9899215/ /pubmed/36739273 http://dx.doi.org/10.1038/s41467-023-36168-x Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Whitlock, Jarred M.
Leikina, Evgenia
Melikov, Kamran
De Castro, Luis Fernandez
Mattijssen, Sandy
Maraia, Richard J.
Collins, Michael T.
Chernomordik, Leonid V.
Cell surface-bound La protein regulates the cell fusion stage of osteoclastogenesis
title Cell surface-bound La protein regulates the cell fusion stage of osteoclastogenesis
title_full Cell surface-bound La protein regulates the cell fusion stage of osteoclastogenesis
title_fullStr Cell surface-bound La protein regulates the cell fusion stage of osteoclastogenesis
title_full_unstemmed Cell surface-bound La protein regulates the cell fusion stage of osteoclastogenesis
title_short Cell surface-bound La protein regulates the cell fusion stage of osteoclastogenesis
title_sort cell surface-bound la protein regulates the cell fusion stage of osteoclastogenesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9899215/
https://www.ncbi.nlm.nih.gov/pubmed/36739273
http://dx.doi.org/10.1038/s41467-023-36168-x
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