Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/111092
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Type: Journal article
Title: USP9X deubiquitylating enzyme maintains RAPTOR protein levels, mTORC1 signalling and proliferation in neural progenitors
Author: Bridges, C.
Tan, M.
Premarathne, S.
Nanayakkara, D.
Bellette, B.
Zencak, D.
Domingo, D.
Gecz, J.
Murtaza, M.
Jolly, L.
Wood, S.
Citation: Scientific Reports, 2017; 7(1):391-1-391-15
Publisher: Nature Publishing Group
Issue Date: 2017
ISSN: 2045-2322
2045-2322
Statement of
Responsibility: 
Caitlin R. Bridges, Men-Chee Tan, Susitha Premarathne, Devathri Nanayakkara, Bernadette Bellette, Dusan Zencak, Deepti Domingo, Jozef Gecz, Mariyam Murtaza, Lachlan A. Jolly and Stephen A. Wood
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.
Keywords: Animals; Humans; Mice; Ubiquitin Thiolesterase; Endopeptidases; Signal Transduction; HEK293 Cells; Neural Stem Cells; Proteolysis; Cell Cycle Checkpoints; Cell Self Renewal; Mechanistic Target of Rapamycin Complex 1; Regulatory-Associated Protein of mTOR
Rights: © The Author(s) 2017 This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
RMID: 0030067403
DOI: 10.1038/s41598-017-00149-0
Grant ID: http://purl.org/au-research/grants/nhmrc/1009248
http://purl.org/au-research/grants/nhmrc/628952
http://purl.org/au-research/grants/nhmrc/1041920
Appears in Collections:Medicine publications

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