HSB-1/HSF-1 pathway modulates histone H4 in mitochondria to control mtDNA transcription and longevity.
Surojit SuralChung-Yi LiangFeng-Yung WangTsui-Ting ChingAo-Lin HsuPublished in: Science advances (2020)
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 Caenorhabditis elegans 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.
Keyphrases
- heat shock
- mitochondrial dna
- copy number
- transcription factor
- genome wide
- gene expression
- heat stress
- heat shock protein
- dna methylation
- oxidative stress
- binding protein
- cell proliferation
- signaling pathway
- genome wide identification
- dna damage
- endoplasmic reticulum stress
- drosophila melanogaster
- cell death
- protein protein
- bioinformatics analysis