USP9X deubiquitylating enzyme maintains RAPTOR protein levels, mTORC1 signalling and proliferation in neural progenitors

Abstract USP9X, is highly expressed in neural progenitors and, essential for neural development in mice. In humans, mutations in USP9X are associated with neurodevelopmental disorders. To understand USP9X’s role in neural progenitors, we studied the effects of altering its expression in both the hum...

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Autores principales:	Caitlin R. Bridges, Men-Chee Tan, Susitha Premarathne, Devathri Nanayakkara, Bernadette Bellette, Dusan Zencak, Deepti Domingo, Jozef Gecz, Mariyam Murtaza, Lachlan A. Jolly, Stephen A. Wood
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3875301c2acd42c798212b993e1de71a
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spelling	oai:doaj.org-article:3875301c2acd42c798212b993e1de71a2021-12-02T11:52:23ZUSP9X deubiquitylating enzyme maintains RAPTOR protein levels, mTORC1 signalling and proliferation in neural progenitors10.1038/s41598-017-00149-02045-2322https://doaj.org/article/3875301c2acd42c798212b993e1de71a2017-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00149-0https://doaj.org/toc/2045-2322Abstract USP9X, is highly expressed in neural progenitors and, essential for neural development in mice. In humans, mutations in USP9X are associated with neurodevelopmental disorders. To understand USP9X’s role in neural progenitors, we studied the effects of altering its expression in both the human neural progenitor cell line, ReNcell VM, as well as neural stem and progenitor cells derived from Nestin-cre conditionally deleted Usp9x mice. Decreasing USP9X resulted in ReNcell VM cells arresting in G0 cell cycle phase, with a concomitant decrease in mTORC1 signalling, a major regulator of G0/G1 cell cycle progression. Decreased mTORC1 signalling was also observed in Usp9x-null neurospheres and embryonic mouse brains. Further analyses revealed, (i) the canonical mTORC1 protein, RAPTOR, physically associates with Usp9x in embryonic brains, (ii) RAPTOR protein level is directly proportional to USP9X, in both loss- and gain-of-function experiments in cultured cells and, (iii) USP9X deubiquitlyating activity opposes the proteasomal degradation of RAPTOR. EdU incorporation assays confirmed Usp9x maintains the proliferation of neural progenitors similar to Raptor-null and rapamycin-treated neurospheres. Interestingly, loss of Usp9x increased the number of sphere-forming cells consistent with enhanced neural stem cell self-renewal. To our knowledge, USP9X is the first deubiquitylating enzyme shown to stabilize RAPTOR.Caitlin R. BridgesMen-Chee TanSusitha PremarathneDevathri NanayakkaraBernadette BelletteDusan ZencakDeepti DomingoJozef GeczMariyam MurtazaLachlan A. JollyStephen A. WoodNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-15 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Caitlin R. Bridges Men-Chee Tan Susitha Premarathne Devathri Nanayakkara Bernadette Bellette Dusan Zencak Deepti Domingo Jozef Gecz Mariyam Murtaza Lachlan A. Jolly Stephen A. Wood USP9X deubiquitylating enzyme maintains RAPTOR protein levels, mTORC1 signalling and proliferation in neural progenitors
description	Abstract USP9X, is highly expressed in neural progenitors and, essential for neural development in mice. In humans, mutations in USP9X are associated with neurodevelopmental disorders. To understand USP9X’s role in neural progenitors, we studied the effects of altering its expression in both the human neural progenitor cell line, ReNcell VM, as well as neural stem and progenitor cells derived from Nestin-cre conditionally deleted Usp9x mice. Decreasing USP9X resulted in ReNcell VM cells arresting in G0 cell cycle phase, with a concomitant decrease in mTORC1 signalling, a major regulator of G0/G1 cell cycle progression. Decreased mTORC1 signalling was also observed in Usp9x-null neurospheres and embryonic mouse brains. Further analyses revealed, (i) the canonical mTORC1 protein, RAPTOR, physically associates with Usp9x in embryonic brains, (ii) RAPTOR protein level is directly proportional to USP9X, in both loss- and gain-of-function experiments in cultured cells and, (iii) USP9X deubiquitlyating activity opposes the proteasomal degradation of RAPTOR. EdU incorporation assays confirmed Usp9x maintains the proliferation of neural progenitors similar to Raptor-null and rapamycin-treated neurospheres. Interestingly, loss of Usp9x increased the number of sphere-forming cells consistent with enhanced neural stem cell self-renewal. To our knowledge, USP9X is the first deubiquitylating enzyme shown to stabilize RAPTOR.
format	article
author	Caitlin R. Bridges Men-Chee Tan Susitha Premarathne Devathri Nanayakkara Bernadette Bellette Dusan Zencak Deepti Domingo Jozef Gecz Mariyam Murtaza Lachlan A. Jolly Stephen A. Wood
author_facet	Caitlin R. Bridges Men-Chee Tan Susitha Premarathne Devathri Nanayakkara Bernadette Bellette Dusan Zencak Deepti Domingo Jozef Gecz Mariyam Murtaza Lachlan A. Jolly Stephen A. Wood
author_sort	Caitlin R. Bridges
title	USP9X deubiquitylating enzyme maintains RAPTOR protein levels, mTORC1 signalling and proliferation in neural progenitors
title_short	USP9X deubiquitylating enzyme maintains RAPTOR protein levels, mTORC1 signalling and proliferation in neural progenitors
title_full	USP9X deubiquitylating enzyme maintains RAPTOR protein levels, mTORC1 signalling and proliferation in neural progenitors
title_fullStr	USP9X deubiquitylating enzyme maintains RAPTOR protein levels, mTORC1 signalling and proliferation in neural progenitors
title_full_unstemmed	USP9X deubiquitylating enzyme maintains RAPTOR protein levels, mTORC1 signalling and proliferation in neural progenitors
title_sort	usp9x deubiquitylating enzyme maintains raptor protein levels, mtorc1 signalling and proliferation in neural progenitors
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/3875301c2acd42c798212b993e1de71a
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USP9X deubiquitylating enzyme maintains RAPTOR protein levels, mTORC1 signalling and proliferation in neural progenitors

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