HSB-1/HSF-1 pathway modulates histone H4 in mitochondria to control mtDNA transcription and longevity

Heat shock factor-1 (HSF-1) is a master regulator of stress responses across taxa. Overexpression of HSF-1 or genetic ablation of its conserved negative regulator, heat shock factor binding protein 1 (HSB-1), results in robust life-span extension in Here, we found that increased HSF-1 activity eleva...

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Published in:Science advances 2020-10, Vol.6 (43)
Main Authors: Sural, Surojit, Liang, Chung-Yi, Wang, Feng-Yung, Ching, Tsui-Ting, Hsu, Ao-Lin
Format: Article
Language:English
Subjects:
Cell Biology
Organismal Biology
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Summary:Heat shock factor-1 (HSF-1) is a master regulator of stress responses across taxa. Overexpression of HSF-1 or genetic ablation of its conserved negative regulator, heat shock factor binding protein 1 (HSB-1), results in robust life-span extension in Here, we found that increased HSF-1 activity elevates histone H4 levels in somatic tissues during development, while knockdown of H4 completely suppresses HSF-1-mediated longevity. Moreover, overexpression of H4 is sufficient to extend life span. Ablation of HSB-1 induces an H4-dependent increase in micrococcal nuclease protection of both nuclear chromatin and mitochondrial DNA (mtDNA), which consequently results in reduced transcription of mtDNA-encoded complex IV genes, decreased respiratory capacity, and a mitochondrial unfolded protein response-dependent life-span extension. Collectively, our findings reveal a previously unknown role of HSB-1/HSF-1 signaling in modulation of mitochondrial function via mediating histone H4-dependent regulation of mtDNA gene expression and concomitantly acting as a determinant of organismal longevity.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.aaz4452