title: Histone H3 and TORC1 prevent organelle dysfunction and cell death by promoting nuclear retention of HMGB proteins.
abstract: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, UT Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN USA.
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Pathology and Laboratory Medicine, UT Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN USA.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Workman
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Strahl
authors.affiliation: Department of Pathology and Laboratory Medicine, UT Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN USA.
authors.forename: R Nicholas
authors.identifier: 0000-0003-4519-4470
authors.initials: RN
authors.lastname: Laribee
keywords: Apoptosis; Chromatin; High mobility group B; Histone; Necrosis; Target of rapamycin