Histone H3 and TORC1 prevent organelle dysfunction and cell death by promoting nuclear retention of HMGB proteins.

Hongfeng Chen,R Nicholas Laribee,Jason J Workman,Brian D Strahl

doi:10.1186/s13072-016-0083-3

Abstract

BackgroundHow 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.ResultsReducing 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.ConclusionsTORC1 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-016-0083-3) contains supplementary material, which is available to authorized users.

Highlights

How cells respond and adapt to environmental changes, such as nutrient flux, remains poorly understood
Histone H3K37 disruption differentially affects the nuclear localization of specific high mobility group box (HMGB) Our rapamycin-based genetic screens determined that H3K37A sensitized cells to reduced target of rapamycin complex 1 (TORC1) activity [17]
These results suggest that the TORC1 phenotype caused by H3K37A is not due solely to loss of electrostatic charge or post-translational modification, but it is instead due to the impairment of a protein–protein contact at H3K37 due to the incorporation of the small hydrophobic alanine at this position

Summary

Introduction

How cells respond and adapt to environmental changes, such as nutrient flux, remains poorly understood. Conserved nutrient signaling cascades can regulate chromatin to contribute to genome regulation and cell adaptation, yet how they do so is only beginning to be elucidated. In response to changing environmental conditions, such as nutrient fluxes or the presence of stress, eukaryotic cells adapt by modulating chromatin structure and their gene expression programs [1]. Oftentimes, the changes made to chromatin and the subsequent regulation of key transcriptional programs is the endpoint for such environmentally responsive chromatin pathways. While the mechanisms controlling chromatin structure continue to be elucidated, how environmental information is transferred to the chromatin and transcription regulatory apparatus, and its impact on chromatin’s signaling functions, remains poorly understood

Methods

Results

Discussion

Conclusion