The Ubiquitin Proteasome System Is a Key Regulator of Pluripotent Stem Cell Survival and Motor Neuron Differentiation.

Autor: Bax M; Illawarra Health and Medical Research Institute, Northfields Avenue, Wollongong, NSW 2522, Australia. mcb675@uowmail.edu.au.; School of Chemistry and Molecular Bioscience, University of Wollongong, Northfields Avenue, Wollongong, NSW 2522, Australia. mcb675@uowmail.edu.au., McKenna J; School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia. jess.mckenna91@gmail.com., Do-Ha D; Illawarra Health and Medical Research Institute, Northfields Avenue, Wollongong, NSW 2522, Australia. pddh859@uowmail.edu.au.; School of Chemistry and Molecular Bioscience, University of Wollongong, Northfields Avenue, Wollongong, NSW 2522, Australia. pddh859@uowmail.edu.au., Stevens CH; Illawarra Health and Medical Research Institute, Northfields Avenue, Wollongong, NSW 2522, Australia. stevensc@uow.edu.au.; School of Chemistry and Molecular Bioscience, University of Wollongong, Northfields Avenue, Wollongong, NSW 2522, Australia. stevensc@uow.edu.au., Higginbottom S; Illawarra Health and Medical Research Institute, Northfields Avenue, Wollongong, NSW 2522, Australia. sh659@uowmail.edu.au.; School of Chemistry and Molecular Bioscience, University of Wollongong, Northfields Avenue, Wollongong, NSW 2522, Australia. sh659@uowmail.edu.au., Balez R; Illawarra Health and Medical Research Institute, Northfields Avenue, Wollongong, NSW 2522, Australia. rb478@uowmail.edu.au.; School of Chemistry and Molecular Bioscience, University of Wollongong, Northfields Avenue, Wollongong, NSW 2522, Australia. rb478@uowmail.edu.au., Cabral-da-Silva MEC; Illawarra Health and Medical Research Institute, Northfields Avenue, Wollongong, NSW 2522, Australia. mcastro@uow.edu.au.; School of Chemistry and Molecular Bioscience, University of Wollongong, Northfields Avenue, Wollongong, NSW 2522, Australia. mcastro@uow.edu.au., Farrawell NE; Illawarra Health and Medical Research Institute, Northfields Avenue, Wollongong, NSW 2522, Australia. nfarrawe@uow.edu.au.; School of Chemistry and Molecular Bioscience, University of Wollongong, Northfields Avenue, Wollongong, NSW 2522, Australia. nfarrawe@uow.edu.au., Engel M; Illawarra Health and Medical Research Institute, Northfields Avenue, Wollongong, NSW 2522, Australia. mengel@uow.edu.au.; School of Chemistry and Molecular Bioscience, University of Wollongong, Northfields Avenue, Wollongong, NSW 2522, Australia. mengel@uow.edu.au., Poronnik P; School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia. philip.poronnik@sydney.edu.au., Yerbury JJ; Illawarra Health and Medical Research Institute, Northfields Avenue, Wollongong, NSW 2522, Australia. jyerbury@uow.edu.au.; School of Chemistry and Molecular Bioscience, University of Wollongong, Northfields Avenue, Wollongong, NSW 2522, Australia. jyerbury@uow.edu.au., Saunders DN; School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia. d.saunders@unsw.edu.au., Ooi L; Illawarra Health and Medical Research Institute, Northfields Avenue, Wollongong, NSW 2522, Australia. lezanne@uow.edu.au.; School of Chemistry and Molecular Bioscience, University of Wollongong, Northfields Avenue, Wollongong, NSW 2522, Australia. lezanne@uow.edu.au.
Jazyk: angličtina
Zdroj: Cells [Cells] 2019 Jun 13; Vol. 8 (6). Date of Electronic Publication: 2019 Jun 13.
DOI: 10.3390/cells8060581
Abstrakt: The ubiquitin proteasome system (UPS) plays an important role in regulating numerous cellular processes, and a dysfunctional UPS is thought to contribute to motor neuron disease. Consequently, we sought to map the changing ubiquitome in human iPSCs during their pluripotent stage and following differentiation to motor neurons. Ubiquitinomics analysis identified that spliceosomal and ribosomal proteins were more ubiquitylated in pluripotent stem cells, whilst proteins involved in fatty acid metabolism and the cytoskeleton were specifically ubiquitylated in the motor neurons. The UPS regulator, ubiquitin-like modifier activating enzyme 1 (UBA1), was increased 36-fold in the ubiquitome of motor neurons compared to pluripotent stem cells. Thus, we further investigated the functional consequences of inhibiting the UPS and UBA1 on motor neurons. The proteasome inhibitor MG132, or the UBA1-specific inhibitor PYR41, significantly decreased the viability of motor neurons. Consistent with a role of the UPS in maintaining the cytoskeleton and regulating motor neuron differentiation, UBA1 inhibition also reduced neurite length. Pluripotent stem cells were extremely sensitive to MG132, showing toxicity at nanomolar concentrations. The motor neurons were more resilient to MG132 than pluripotent stem cells but demonstrated higher sensitivity than fibroblasts. Together, this data highlights the important regulatory role of the UPS in pluripotent stem cell survival and motor neuron differentiation.
Databáze: MEDLINE
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