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The role of the ubiquitin proteasome system in eliminating misfolded proteins
Damaged and misfolded proteins that cannot be fixed have to be eliminated in the cell. Failure to do so leads to the accumulation of these proteins that will then aggregate. Protein aggregation is a hallmark of a large number of neurodegenerative pathologies including Parkinson’s and Prion diseases. The ubiquitin proteasome system pays a major role in targeting aberrant proteins for proteolysis. In this system, target proteins are first modified by the covalent attachment of ubiquitin (i.e., ubiquitylation) and then recognized and degraded by the proteasome. Using a combination of cell biology and proteomics, our lab is interested in understanding how the cell recognizes these misfolded proteins to target them for ubiquitylation and proteolysis. Better insight into these pathways may lead to a major breakthrough in the understanding of some neurodegenerative diseases.
Future projects for prospective students and postdocs
The Mayor lab is looking for new graduate students and postdocs. Future projects include the following proposed studies: 1) to further delineate the recognition and targeting mechanisms of misfolded proteins at the molecular level using reconstituted in vitro systems, 2) to further characterize the heat shock ubiquitylation response in mammalian tissue culture cells, 3) to screen for novel quality control pathways in mammalian tissue culture cells, 4) to develop proteomics approaches to determine which proteins are more prone to misfolding and aggregation, and 5) to employ proteomics approaches to probe the changes in proteostasis upon aging. Additional projects in the area of ubiquitylation, proteasome degradation, protein misfolding, and protein aggregation could also be further developed for motivated candidates. For more information, contact directly Dr. Thibault Mayor.
Deubiquitinase activity is required for the proteasomal degradation of misfolded cytosolic proteins upon heat-stress.Fang NN, Zhu M, Rose A, Wu KP, Mayor T. Nature Communications In press
Prefoldin Promotes Proteasomal Degradation of Cytosolic Proteins with Missense Mutations by Maintaining Substrate Solubility. Comyn SA, Young BP, Loewen CJ, Mayor T. PLoS Genetics (2016) 12(7):e1006184.
A feature analysis of lower solubility proteins in three eukaryotic systems. Albu RF, Chan GT, Zhu M, Wong ET, Taghizadeh F, Hu X, Mehran AE, Johnson JD, Gsponer J, Mayor T. J Proteomics (2015) 118:21-38.
Rsp5/Nedd4 is the main ubiquitin ligase that targets cytosolic misfolded proteins following heat stress.
Fang NN, Chan GT, Zhu M, Comyn SA, Persaud A, Deshaies RJ, Rotin D, Gsponer J, Mayor T. Nat Cell Biol. (2014) 16(12):1227-37
Polarization of the endoplasmic reticulum by ER-septin tethering. Chao JT, Wong AK, Tavassoli S, Young BP, Chruscicki A, Fang NN, Howe LJ, Mayor T, Foster LJ, Loewen CJ. Cell (2014) 158(3):620-32
Perilous journey: a tour of the ubiquitin-proteasome system. Kleiger G and Mayor T. Trends Cell Biol. (2014) 24(6):352-359
False start: cotranslational protein ubiquitination and cytosolic protein quality control. Comyn SA, Chan GT, Mayor T. J Proteomics (2014) 100:92-101
System-Wide Analysis Reveals Intrinsically Disordered Proteins are Prone to Ubiquitylation after Misfolding Stress. Ng AH, Fang NN, Comyn SA, Gsponer J, Mayor T. Mol. Cell. Proteomics (2013) 12(9):2456-67
The Yeast Ubr1 Ubiquitin Ligase Participates in a Prominent Pathway That Targets Cytosolic Thermosensitive Mutants for Degradation. Khosrow-Khavar F, Fang NN, Ng AH, Winget JM, Comyn SA, Mayor T. G3 (2012) 2:619-628
Hul5 HECT ubiquitin ligase plays a major role in the ubiquitylation and turnover of cytosolic misfolded proteins. Fang NN, Ng AH, Measday V, Mayor T. Nature Cell Biology (2011) 13(11):1344-52
Proteomic characterization of aggregating proteins after the inhibition of the ubiquitin proteasome system.
Wilde I, Brack M, Winget JM, Mayor T. Journal Proteome Research (2011) 10(3):1062-72
Niclosamide prevents the formation of large ubiquitin-containing aggregates caused by proteasome inhibition.
Gies E, Wilde I, Winget JM, Brack M, Rotblat B, Arias Novoa C, Balgi AD, Sorensen PH, Roberge M, Mayor T. PLoS ONE (2010) 5(12):e14410
The Diversity of Ubiquitin Recognition: Hot Spots and Varied Speciﬁcity. Winget JM and Mayor T. Molecular Cell (2010) 38: 627-635