A significant correlation has been observed between the length of the polyglutamine tract in huntingtin, its aggregation and the progression of Huntington's disease (HD). The chaperonin TRiC is a potent antagonist of aggregation of mutant huntingtin. Using the well-validated Saccharomyces cerevisiae model of HD, we have investigated the role of age-related post-translational modifications of this heterooligomeric chaperonin on its ability to inhibit aggregation of the mutant protein. We show that the glycerol synthetic enzyme Gpd1 is involved in the post-translational modification of Tcp-1 (subunit of TRiC) by acetylation and glycation through the NAD(+)/NADH shuttle and the triose phosphate intermediate dihydroxyacetone phosphate, respectively. The extent of modification of Tcp-1 shows a negative correlation with the solubility of mutant huntingtin. The absence of Gpd1 also induces heat shock response in yeast cells, further inhibiting aggregation of the mutant protein. Thus, Gpd1 acts as a major regulator of the protein folding machinery in the yeast model of HD. Modification and inactivation of cellular chaperonin are accelerated in an aging cell, which has further deleterious effects for a cell harbouring misfolded/aggregated protein(s).
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Evidence ID | Analyze ID | Gene/Complex | Systematic Name/Complex Accession | Qualifier | Gene Ontology Term ID | Gene Ontology Term | Aspect | Annotation Extension | Evidence | Method | Source | Assigned On | Reference |
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Evidence ID | Analyze ID | Gene | Gene Systematic Name | Phenotype | Experiment Type | Experiment Type Category | Mutant Information | Strain Background | Chemical | Details | Reference |
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Evidence ID | Analyze ID | Gene | Gene Systematic Name | Disease Ontology Term | Disease Ontology Term ID | Qualifier | Evidence | Method | Source | Assigned On | Reference |
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Evidence ID | Analyze ID | Regulator | Regulator Systematic Name | Target | Target Systematic Name | Direction | Regulation of | Happens During | Regulator Type | Direction | Regulation Of | Happens During | Method | Evidence | Strain Background | Reference |
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Site | Modification | Modifier | Source | Reference |
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Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Allele | Assay | Annotation | Action | Phenotype | SGA score | P-value | Source | Reference | Note |
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Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Assay | Annotation | Action | Modification | Source | Reference | Note |
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Complement ID | Locus ID | Gene | Species | Gene ID | Strain background | Direction | Details | Source | Reference |
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Evidence ID | Analyze ID | Dataset | Description | Keywords | Number of Conditions | Reference |
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Evidence ID | Analyze ID | File | Description |
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