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USP18 is an essential regulator of muscle cell differentiation and maturation

The ubiquitin proteasomal system is a critical regulator of muscle physiology, and impaired UPS is key in many muscle pathologies. Yet, little is known about the function of deubiquitinating enzymes (DUBs) in the muscle cell context. We performed a genetic screen to identify DUBs as potential regula...

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Autores principales: Olie, Cyriel Sebastiaan, Pinto-Fernández, Adán, Damianou, Andreas, Vendrell, Iolanda, Mei, Hailiang, den Hamer, Bianca, van der Wal, Erik, de Greef, Jessica C., Raz, Vered, Kessler, Benedikt M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10066380/
https://www.ncbi.nlm.nih.gov/pubmed/37002195
http://dx.doi.org/10.1038/s41419-023-05725-z
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author Olie, Cyriel Sebastiaan
Pinto-Fernández, Adán
Damianou, Andreas
Vendrell, Iolanda
Mei, Hailiang
den Hamer, Bianca
van der Wal, Erik
de Greef, Jessica C.
Raz, Vered
Kessler, Benedikt M.
author_facet Olie, Cyriel Sebastiaan
Pinto-Fernández, Adán
Damianou, Andreas
Vendrell, Iolanda
Mei, Hailiang
den Hamer, Bianca
van der Wal, Erik
de Greef, Jessica C.
Raz, Vered
Kessler, Benedikt M.
author_sort Olie, Cyriel Sebastiaan
collection PubMed
description The ubiquitin proteasomal system is a critical regulator of muscle physiology, and impaired UPS is key in many muscle pathologies. Yet, little is known about the function of deubiquitinating enzymes (DUBs) in the muscle cell context. We performed a genetic screen to identify DUBs as potential regulators of muscle cell differentiation. Surprisingly, we observed that the depletion of ubiquitin-specific protease 18 (USP18) affected the differentiation of muscle cells. USP18 depletion first stimulated differentiation initiation. Later, during differentiation, the absence of USP18 expression abrogated myotube maintenance. USP18 enzymatic function typically attenuates the immune response by removing interferon-stimulated gene 15 (ISG15) from protein substrates. However, in muscle cells, we found that USP18, predominantly nuclear, regulates differentiation independent of ISG15 and the ISG response. Exploring the pattern of RNA expression profiles and protein networks whose levels depend on USP18 expression, we found that differentiation initiation was concomitant with reduced expression of the cell-cycle gene network and altered expression of myogenic transcription (co) factors. We show that USP18 depletion altered the calcium channel gene network, resulting in reduced calcium flux in myotubes. Additionally, we show that reduced expression of sarcomeric proteins in the USP18 proteome was consistent with reduced contractile force in an engineered muscle model. Our results revealed nuclear USP18 as a critical regulator of differentiation initiation and maintenance, independent of ISG15 and its role in the ISG response.
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spelling pubmed-100663802023-04-02 USP18 is an essential regulator of muscle cell differentiation and maturation Olie, Cyriel Sebastiaan Pinto-Fernández, Adán Damianou, Andreas Vendrell, Iolanda Mei, Hailiang den Hamer, Bianca van der Wal, Erik de Greef, Jessica C. Raz, Vered Kessler, Benedikt M. Cell Death Dis Article The ubiquitin proteasomal system is a critical regulator of muscle physiology, and impaired UPS is key in many muscle pathologies. Yet, little is known about the function of deubiquitinating enzymes (DUBs) in the muscle cell context. We performed a genetic screen to identify DUBs as potential regulators of muscle cell differentiation. Surprisingly, we observed that the depletion of ubiquitin-specific protease 18 (USP18) affected the differentiation of muscle cells. USP18 depletion first stimulated differentiation initiation. Later, during differentiation, the absence of USP18 expression abrogated myotube maintenance. USP18 enzymatic function typically attenuates the immune response by removing interferon-stimulated gene 15 (ISG15) from protein substrates. However, in muscle cells, we found that USP18, predominantly nuclear, regulates differentiation independent of ISG15 and the ISG response. Exploring the pattern of RNA expression profiles and protein networks whose levels depend on USP18 expression, we found that differentiation initiation was concomitant with reduced expression of the cell-cycle gene network and altered expression of myogenic transcription (co) factors. We show that USP18 depletion altered the calcium channel gene network, resulting in reduced calcium flux in myotubes. Additionally, we show that reduced expression of sarcomeric proteins in the USP18 proteome was consistent with reduced contractile force in an engineered muscle model. Our results revealed nuclear USP18 as a critical regulator of differentiation initiation and maintenance, independent of ISG15 and its role in the ISG response. Nature Publishing Group UK 2023-03-31 /pmc/articles/PMC10066380/ /pubmed/37002195 http://dx.doi.org/10.1038/s41419-023-05725-z Text en © The Author(s) 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
Olie, Cyriel Sebastiaan
Pinto-Fernández, Adán
Damianou, Andreas
Vendrell, Iolanda
Mei, Hailiang
den Hamer, Bianca
van der Wal, Erik
de Greef, Jessica C.
Raz, Vered
Kessler, Benedikt M.
USP18 is an essential regulator of muscle cell differentiation and maturation
title USP18 is an essential regulator of muscle cell differentiation and maturation
title_full USP18 is an essential regulator of muscle cell differentiation and maturation
title_fullStr USP18 is an essential regulator of muscle cell differentiation and maturation
title_full_unstemmed USP18 is an essential regulator of muscle cell differentiation and maturation
title_short USP18 is an essential regulator of muscle cell differentiation and maturation
title_sort usp18 is an essential regulator of muscle cell differentiation and maturation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10066380/
https://www.ncbi.nlm.nih.gov/pubmed/37002195
http://dx.doi.org/10.1038/s41419-023-05725-z
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