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

2020 ◽  
Vol 6 (43) ◽  
pp. eaaz4452
Author(s):  
Surojit Sural ◽  
Chung-Yi Liang ◽  
Feng-Yung Wang ◽  
Tsui-Ting Ching ◽  
Ao-Lin Hsu
Keyword(s):  
Heat Shock ◽  
Life Span ◽  
Stress Responses ◽  
Heat Shock Factor ◽  
Negative Regulator ◽  
Micrococcal Nuclease ◽  
Heat Shock Factor 1 ◽  
Histone H4 ◽  
Life Span Extension ◽  
Genetic Ablation

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 Caenorhabditiselegans. 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.

scholarly journals HSB-1 inhibition and HSF-1 overexpression trigger overlapping transcriptional changes to promote longevity in Caenorhabditis elegans

2019 ◽  
Author(s):  
Surojit Sural ◽  
Tzu-Chiao Lu ◽  
Seung Ah Jung ◽  
Ao-Lin Hsu
Keyword(s):  
Heat Shock ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Heat Shock Factor ◽  
Binding Activity ◽  
Negative Regulator ◽  
Target Sequence ◽  
Heat Shock Factor 1 ◽  
Altered Expression ◽  
Genetic Ablation

ABSTRACTHeat shock factor 1 (HSF-1) is a component of the heat shock response pathway that is induced by cytoplasmic proteotoxic stress. In addition to its role in stress response, HSF-1 also acts as a key regulator of the rate of organismal aging. Overexpression of HSF-1 promotes longevity in C. elegans via mechanisms that remain less understood. Moreover, genetic ablation of a negative regulator of HSF-1, termed as heat shock factor binding protein 1 (HSB-1), results in hsf-1-dependent life span extension in animals. Here we show that in the absence of HSB-1, HSF-1 acquires increased DNA binding activity to its genomic target sequence. Using RNA-Seq to compare the gene expression profiles of the hsb-1 mutant and hsf-1 overexpression strains, we found that while more than 1,500 transcripts show ≥1.5-fold upregulation due to HSF-1 overexpression, HSB-1 inhibition alters the expression of less than 500 genes in C. elegans. Roughly half of the differentially regulated transcripts in the hsb-1 mutant have altered expression also in hsf-1 overexpressing animals, with a strongly correlated fold-expression pattern between the two strains. In addition, genes that are upregulated via both HSB-1 inhibition and HSF-1 overexpression include numerous DAF-16 targets that have known functions in longevity regulation. This study identifies how HSB-1 acts as a specific regulator of the transactivation potential of HSF-1 in non-stressed conditions, thus providing a detailed understanding of the role of HSB-1/HSF-1 signaling pathway in transcriptional regulation and longevity in C. elegans.

scholarly journals Heat Shock Factor 1 Is a Substrate for p38 Mitogen-Activated Protein Kinases

2016 ◽  
Vol 36 (18) ◽  
pp. 2403-2417 ◽  
Author(s):  
Sharadha Dayalan Naidu ◽  
Calum Sutherland ◽  
Ying Zhang ◽  
Ana Risco ◽  
Laureano de la Vega ◽  
...  
Keyword(s):  
Heat Shock ◽  
P38 Mapk ◽  
Nuclear Translocation ◽  
Heat Shock Factor ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Luciferase Reporter ◽  
Heat Shock Factor 1 ◽  
Mitogen Activated Protein ◽  
P38 Mapks

Heat shock factor 1 (HSF1) monitors the structural integrity of the proteome. Phosphorylation at S326 is a hallmark for HSF1 activation, but the identity of the kinase(s) phosphorylating this site has remained elusive. We show here that the dietary agent phenethyl isothiocyanate (PEITC) inhibits heat shock protein 90 (Hsp90), the main negative regulator of HSF1; activates p38 mitogen-activated protein kinase (MAPK); and increases S326 phosphorylation, trimerization, and nuclear translocation of HSF1, and the transcription of a luciferase reporter, as well as the endogenous prototypic HSF1 target Hsp70.In vitro, all members of the p38 MAPK family rapidly and stoichiometrically catalyze the S326 phosphorylation. The use of stable knockdown cell lines and inhibitors indicated that among the p38 MAPKs, p38γ is the principal isoform responsible for the phosphorylation of HSF1 at S326 in cells. A protease-mass spectrometry approach confirmed S326 phosphorylation and unexpectedly revealed that p38 MAPK also catalyzes the phosphorylation of HSF1 at S303/307, previously known repressive posttranslational modifications. Thus, we have identified p38 MAPKs as highly efficient catalysts for the phosphorylation of HSF1. Furthermore, our findings suggest that the magnitude and persistence of activation of p38 MAPK are important determinants of the extent and duration of the heat shock response.

scholarly journals Effects of neurohormonal stress and aging on the activation of mammalian heat shock factor 1.

1994 ◽  
Vol 269 (51) ◽  
pp. 32272-32278
Author(s):  
T W Fawcett ◽  
S L Sylvester ◽  
K D Sarge ◽  
R I Morimoto ◽  
N J Holbrook
Keyword(s):  
Heat Shock ◽  
Heat Shock Factor ◽  
Heat Shock Factor 1

scholarly journals Phosphorylation of Serine 303 Is a Prerequisite for the Stress-Inducible SUMO Modification of Heat Shock Factor 1

2003 ◽  
Vol 23 (8) ◽  
pp. 2953-2968 ◽  
Author(s):  
Ville Hietakangas ◽  
Johanna K. Ahlskog ◽  
Annika M. Jakobsson ◽  
Maria Hellesuo ◽  
Niko M. Sahlberg ◽  
...  
Keyword(s):  
Heat Shock ◽  
Phosphorylation Site ◽  
Stress Granules ◽  
Heat Shock Factor ◽  
Transcriptional Level ◽  
Heat Shock Factor 1 ◽  
Protection Mechanism ◽  
Sumo Modification

ABSTRACT The heat shock response, which is accompanied by a rapid and robust upregulation of heat shock proteins (Hsps), is a highly conserved protection mechanism against protein-damaging stress. Hsp induction is mainly regulated at transcriptional level by stress-inducible heat shock factor 1 (HSF1). Upon activation, HSF1 trimerizes, binds to DNA, concentrates in the nuclear stress granules, and undergoes a marked multisite phosphorylation, which correlates with its transcriptional activity. In this study, we show that HSF1 is modified by SUMO-1 and SUMO-2 in a stress-inducible manner. Sumoylation is rapidly and transiently enhanced on lysine 298, located in the regulatory domain of HSF1, adjacent to several critical phosphorylation sites. Sumoylation analyses of HSF1 phosphorylation site mutants reveal that specifically the phosphorylation-deficient S303 mutant remains devoid of SUMO modification in vivo and the mutant mimicking phosphorylation of S303 promotes HSF1 sumoylation in vitro, indicating that S303 phosphorylation is required for K298 sumoylation. This finding is further supported by phosphopeptide mapping and analysis with S303/7 phosphospecific antibodies, which demonstrate that serine 303 is a target for strong heat-inducible phosphorylation, corresponding to the inducible HSF1 sumoylation. A transient phosphorylation-dependent colocalization of HSF1 and SUMO-1 in nuclear stress granules provides evidence for a strictly regulated subnuclear interplay between HSF1 and SUMO.

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