Background: How cells respond and adapt to environmental changes, such as nutrient flux, remains poorly understood. Evolutionarily conserved nutrient signaling cascades can regulate chromatin to contribute to genome regulation and cell adaptation, yet how they do so is only now beginning to be elucidated. In this study, we provide evidence in yeast that the conserved nutrient regulated target of rapamycin complex 1 (TORC1) pathway, and the histone H3N-terminus at lysine 37 (H3K37), function collaboratively to restrict specific chromatin-binding high mobility group box (HMGB) proteins to the nucleus to maintain cellular homeostasis and viability.
Results: Reducing TORC1 activity in an H3K37 mutant causes cytoplasmic localization of the HMGB Nhp6a, organelle dysfunction, and both non-traditional apoptosis and necrosis. Surprisingly, under nutrient-rich conditions the H3K37 mutation increases basal TORC1 signaling. This effect is prevented by individual deletion of the genes encoding HMGBs whose cytoplasmic localization increases when TORC1 activity is repressed. This increased TORC1 signaling also can be replicated in cells by overexpressing the same HMGBs, thus demonstrating a direct and unexpected role for HMGBs in modulating TORC1 activity. The physiological consequence of impaired HMGB nuclear localization is an increased dependence on TORC1 signaling to maintain viability, an effect that ultimately reduces the chronological longevity of H3K37 mutant cells under limiting nutrient conditions.
Conclusions: TORC1 and histone H3 collaborate to retain HMGBs within the nucleus to maintain cell homeostasis and promote longevity. As TORC1, HMGBs, and H3 are evolutionarily conserved, our study suggests that functional interactions between the TORC1 pathway and histone H3 in metazoans may play a similar role in the maintenance of homeostasis and aging regulation.
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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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