The E3 Ubiquitin Ligase SCF Cyclin F Promotes Sequestosome-1/p62 Insolubility and Foci Formation and is Dysregulated in ALS and FTD Pathogenesis.

Autor: Davidson JM; Centre for Motor Neuron Disease Research, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Level 1, 75 Talavera Road, Sydney, NSW, 2109, Australia. jennilee.davidson@mq.edu.au., Wu SSL; Centre for Motor Neuron Disease Research, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Level 1, 75 Talavera Road, Sydney, NSW, 2109, Australia., Rayner SL; Centre for Motor Neuron Disease Research, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Level 1, 75 Talavera Road, Sydney, NSW, 2109, Australia., Cheng F; Centre for Motor Neuron Disease Research, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Level 1, 75 Talavera Road, Sydney, NSW, 2109, Australia., Duncan K; Centre for Motor Neuron Disease Research, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Level 1, 75 Talavera Road, Sydney, NSW, 2109, Australia., Russo C; Computational NeuroSurgery (CNS) Lab, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Level 1, 75 Talavera Road, Sydney, NSW, 2109, Australia., Newbery M; Illawarra Health and Medical Research Institute, Northfields Avenue, Wollongong, NSW, 2522, Australia.; School of Chemistry and Molecular Bioscience and Molecular Horizons, University of Wollongong, Northfields Avenue, Wollongong, NSW, 2522, Australia., Ding K; Centre for Motor Neuron Disease Research, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Level 1, 75 Talavera Road, Sydney, NSW, 2109, Australia., Scherer NM; Centre for Motor Neuron Disease Research, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Level 1, 75 Talavera Road, Sydney, NSW, 2109, Australia., Balez R; Illawarra Health and Medical Research Institute, Northfields Avenue, Wollongong, NSW, 2522, Australia.; School of Chemistry and Molecular Bioscience and Molecular Horizons, University of Wollongong, Northfields Avenue, Wollongong, NSW, 2522, Australia., García-Redondo A; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER U-723), Unidad de ELA, Instituto de Investigación Hospital 12 de Octubre de Madrid, SERMAS, Madrid, Spain., Rábano A; Neuropathology Department and CIEN Tissue Bank, Alzheimer's Centre Reina Sofia-CIEN Foundation, 28031, Madrid, Spain., Rosa-Fernandes L; Centre for Motor Neuron Disease Research, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Level 1, 75 Talavera Road, Sydney, NSW, 2109, Australia., Ooi L; Illawarra Health and Medical Research Institute, Northfields Avenue, Wollongong, NSW, 2522, Australia.; School of Chemistry and Molecular Bioscience and Molecular Horizons, University of Wollongong, Northfields Avenue, Wollongong, NSW, 2522, Australia., Williams KL; Centre for Motor Neuron Disease Research, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Level 1, 75 Talavera Road, Sydney, NSW, 2109, Australia., Morsch M; Centre for Motor Neuron Disease Research, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Level 1, 75 Talavera Road, Sydney, NSW, 2109, Australia., Blair IP; Centre for Motor Neuron Disease Research, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Level 1, 75 Talavera Road, Sydney, NSW, 2109, Australia., Di Ieva A; Computational NeuroSurgery (CNS) Lab, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Level 1, 75 Talavera Road, Sydney, NSW, 2109, Australia., Yang S; Centre for Motor Neuron Disease Research, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Level 1, 75 Talavera Road, Sydney, NSW, 2109, Australia., Chung RS; Centre for Motor Neuron Disease Research, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Level 1, 75 Talavera Road, Sydney, NSW, 2109, Australia., Lee A; Centre for Motor Neuron Disease Research, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Level 1, 75 Talavera Road, Sydney, NSW, 2109, Australia.
Jazyk: angličtina
Zdroj: Molecular neurobiology [Mol Neurobiol] 2023 Sep; Vol. 60 (9), pp. 5034-5054. Date of Electronic Publication: 2023 May 27.
DOI: 10.1007/s12035-023-03355-2
Abstrakt: Amyotrophic lateral sclerosis (ALS)- and frontotemporal dementia (FTD)-linked mutations in CCNF have been shown to cause dysregulation to protein homeostasis. CCNF encodes for cyclin F, which is part of the cyclin F-E3 ligase complex SCF cyclinF known to ubiquitylate substrates for proteasomal degradation. In this study, we identified a function of cyclin F to regulate substrate solubility and show how cyclin F mechanistically underlies ALS and FTD disease pathogenesis. We demonstrated that ALS and FTD-associated protein sequestosome-1/p62 (p62) was a canonical substrate of cyclin F which was ubiquitylated by the SCF cyclinF complex. We found that SCF cyclin F ubiquitylated p62 at lysine(K)281, and that K281 regulated the propensity of p62 to aggregate. Further, cyclin F expression promoted the aggregation of p62 into the insoluble fraction, which corresponded to an increased number of p62 foci. Notably, ALS and FTD-linked mutant cyclin F p.S621G aberrantly ubiquitylated p62, dysregulated p62 solubility in neuronal-like cells, patient-derived fibroblasts and induced pluripotent stem cells and dysregulated p62 foci formation. Consistently, motor neurons from patient spinal cord tissue exhibited increased p62 ubiquitylation. We suggest that the p.S621G mutation impairs the functions of cyclin F to promote p62 foci formation and shift p62 into the insoluble fraction, which may be associated to aberrant mutant cyclin F-mediated ubiquitylation of p62. Given that p62 dysregulation is common across the ALS and FTD spectrum, our study provides insights into p62 regulation and demonstrates that ALS and FTD-linked cyclin F mutant p.S621G can drive p62 pathogenesis associated with ALS and FTD.
(© 2023. The Author(s).)
Databáze: MEDLINE
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