Temporal requirements of SKN-1/NRF as a regulator of lifespan and proteostasis in Caenorhabditis elegans

Lowering the activity of the Insulin/IGF-1 Signaling (IIS) cascade results in elevated stress resistance, enhanced protein homeostasis (proteostasis) and extended lifespan of worms, flies and mice. In the nematode Caenorhabditis elegans (C. elegans), the longevity phenotype that stems from IIS reduction is entirely dependent upon the activities of a subset of transcription factors including the Forkhead factor DAF-16/FOXO (DAF-16), Heat Shock Factor-1 (HSF-1), SKiNhead/Nrf (SKN-1) and ParaQuat Methylviologen responsive (PQM-1). While DAF-16 determines lifespan exclusively during early adulthood and governs proteostasis in early adulthood and midlife, HSF-1 executes these functions foremost during development. Despite the central roles of SKN-1 as a regulator of lifespan and proteostasis, the temporal requirements of this transcription factor were unknown. Here we employed conditional knockdown techniques and discovered that in C. elegans, SKN-1 is primarily important for longevity and proteostasis during late larval development through early adulthood. Our findings indicate that events that occur during late larval developmental through early adulthood affect lifespan and proteostasis and suggest that subsequent to HSF-1, SKN-1 sets the conditions, partially overlapping temporally with DAF-16, that enable IIS reduction to promote longevity and proteostasis. Our findings raise the intriguing possibility that HSF-1, SKN-1 and DAF-16 function in a coordinated and sequential manner to promote healthy aging.

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Temporal Requirements of SKN-1/NRF as a Regulator of Lifespan and Proteostasis in Caenorhabditis elegans

10.1101/2020.11.24.395707 ◽

2020 ◽

Author(s):

Danielle Grushko ◽

Amir Levine ◽

Hana Boocholez ◽

Ehud Cohen

Keyword(s):

Transcription Factor ◽

Transcription Factors ◽

Caenorhabditis Elegans ◽

Stress Resistance ◽

Healthy Aging ◽

Early Adulthood ◽

Protein Homeostasis ◽

Heat Shock Factor 1 ◽

C Elegans ◽

Extended Lifespan

AbstractLowering the activity of the Insulin/IGF-1 Signaling (IIS) cascade results in elevated stress resistance, enhanced protein homeostasis (proteostasis) and extended lifespan of worms, flies and mice. In the nematode Caenorhabditis elegans (C. elegans), the longevity phenotype that stems from IIS reduction is entirely dependent upon the activities of a subset of transcription factors including the Forkhead factor DAF-16/FOXO (DAF-16), Heat Shock Factor-1 (HSF-1), SKiNhead/Nrf (SKN-1) and ParaQuat Methylviologen responsive (PQM-1). While DAF-16 determines lifespan exclusively during early adulthood and governs proteostasis in early adulthood and midlife, HSF-1 executes these functions foremost during development. Despite the central roles of SKN-1 as a regulator of lifespan and proteostasis, the temporal requirements of this transcription factor were unknown. Here we employed conditional knockdown techniques and discovered that in C. elegans, SKN-1 is primarily important for longevity and proteostasis during late larval development through early adulthood. Our findings indicate that events that occur during late larval developmental through early adulthood affect lifespan and proteostasis and suggest that subsequent to HSF-1, SKN-1 sets the conditions, partially overlapping temporally with DAF-16, that enable IIS reduction to promote longevity and proteostasis. Our findings raise the intriguing possibility that HSF-1, SKN-1 and DAF-16 function in a coordinated and sequential manner to promote healthy aging.

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Faculty Opinions recommendation of Distinct stimulus-specific histone modifications at hsp70 chromatin targeted by the transcription factor heat shock factor-1.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1021530.245659 ◽

2004 ◽

Author(s):

Peter B Becker

Keyword(s):

Transcription Factor ◽

Heat Shock ◽

Histone Modifications ◽

Heat Shock Factor ◽

Heat Shock Factor 1

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Faculty Opinions recommendation of Differential display of DNA-binding proteins reveals heat-shock factor 1 as a circadian transcription factor.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1100379.559066 ◽

2008 ◽

Author(s):

Mark Caddick

Keyword(s):

Transcription Factor ◽

Heat Shock ◽

Dna Binding ◽

Differential Display ◽

Binding Proteins ◽

Dna Binding Proteins ◽

Heat Shock Factor ◽

Heat Shock Factor 1 ◽

Circadian Transcription

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Rescue of a developmental arrest caused by a C. elegans heat-shock transcription-factor mutation by loss of ribosomal S6-kinase activity

10.1101/310086 ◽

2018 ◽

Author(s):

Peter Chisnell ◽

T. Richard Parenteau ◽

Elizabeth Tank ◽

Kaveh Ashrafi ◽

Cynthia Kenyon

Keyword(s):

Transcription Factor ◽

Transcription Factors ◽

Heat Shock ◽

Heat Shock Transcription Factor ◽

Adult Longevity ◽

Loss Of Function ◽

S6 Kinase ◽

Heat Shock Transcription Factors ◽

C Elegans ◽

Developmental Arrest

AbstractThe widely conserved heat-shock response, regulated by heat shock transcription factors, is not only essential for cellular stress resistance and adult longevity, but also for proper development. However, the genetic mechanisms by which heat-shock transcription factors regulate development are not well understood. In C. elegans, we conducted an unbiased genetic screen to identify mutations that could ameliorate the developmental arrest phenotype of a heat-shock factor mutant. Here we show that loss of the conserved translational activator rsks-1/S6-Kinase, a downstream effector of TOR kinase, can rescue the developmental-arrest phenotype of hsf-1 partial loss-of-function mutants. Unexpectedly, we show that the rescue is not likely caused by reduced translation, nor to activation of any of a variety of stress-protective genes and pathways. Our findings identify an as-yet unexplained regulatory relationship between the heat-shock transcription factor and the TOR pathway during C. elegans’ development.

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Heat Shock Factor 1 in Protein Homeostasis and Oncogenic Signal Integration

Cancer Research ◽

10.1158/0008-5472.can-14-2905 ◽

2015 ◽

Vol 75 (6) ◽

pp. 907-912 ◽

Cited By ~ 24

Author(s):

Trisha Home ◽

Roy A. Jensen ◽

Rekha Rao

Keyword(s):

Heat Shock ◽

Heat Shock Factor ◽

Protein Homeostasis ◽

Heat Shock Factor 1 ◽

Signal Integration

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Holocentromeres are dispersed point centromeres localized at transcription factor hotspots

eLife ◽

10.7554/elife.02025 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 61

Author(s):

Florian A Steiner ◽

Steven Henikoff

Keyword(s):

Transcription Factor ◽

Transcription Factors ◽

Caenorhabditis Elegans ◽

Binding Sites ◽

Specific Binding ◽

Basic Unit ◽

Centromeric Chromatin ◽

Sequence Composition ◽

Specific Binding Sites ◽

Mechanistic Basis

Centromeres vary greatly in size and sequence composition, ranging from ‘point’ centromeres with a single cenH3-containing nucleosome to ‘regional’ centromeres embedded in tandemly repeated sequences to holocentromeres that extend along the length of entire chromosomes. Point centromeres are defined by sequence, whereas regional and holocentromeres are epigenetically defined by the location of cenH3-containing nucleosomes. In this study, we show that Caenorhabditis elegans holocentromeres are organized as dispersed but discretely localized point centromeres, each forming a single cenH3-containing nucleosome. These centromeric sites co-localize with kinetochore components, and their occupancy is dependent on the cenH3 loading machinery. These sites coincide with non-specific binding sites for multiple transcription factors (‘HOT’ sites), which become occupied when cenH3 is lost. Our results show that the point centromere is the basic unit of holocentric organization in support of the classical polycentric model for holocentromeres, and provide a mechanistic basis for understanding how centromeric chromatin might be maintained.

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Agrimonia procera Wallr. Extract Increases Stress Resistance and Prolongs Life Span in Caenorhabditis elegans via Transcription Factor DAF-16 (FoxO Orthologue)

Antioxidants ◽

10.3390/antiox7120192 ◽

2018 ◽

Vol 7 (12) ◽

pp. 192 ◽

Cited By ~ 2

Author(s):

Christina Saier ◽

Inge Gommlich ◽

Volker Hiemann ◽

Sabrina Baier ◽

Karoline Koch ◽

...

Keyword(s):

Transcription Factor ◽

Caenorhabditis Elegans ◽

Life Span ◽

Stress Resistance ◽

Radical Scavenging Activity ◽

Radical Scavenging ◽

Model Organism ◽

Amyloid Β ◽

Ethanol Extract

Agrimonia procera is a pharmacologically interesting plant which is proposed to protect against various diseases due to its high amount of phytochemicals, e.g., polyphenols. However, in spite of the amount of postulated health benefits, studies concerning the mechanistic effects of Agrimonia procera are limited. Using the nematode Caenorhabditis elegans, we were able to show that an ethanol extract of Agrimonia procera herba (eAE) mediates strong antioxidative effects in the nematode: Beside a strong radical-scavenging activity, eAE reduces accumulation of reactive oxygen species (ROS) accumulation and protects against paraquat-induced oxidative stress. The extract does not protect against amyloid-β-mediated toxicity, but efficiently increases the life span (up to 12.7%), as well as the resistance to thermal stress (prolongation of survival up to 22%), of this model organism. Using nematodes deficient in the forkhead box O (FoxO)-orthologue DAF-16, we were able to demonstrate that beneficial effects of eAE on stress resistance and life span were mediated via this transcription factor. We showed antioxidative, stress-reducing, and life-prolonging effects of eAE in vivo and were able to demonstrate a molecular mechanism of this extract. These results may be important for identifying further molecular targets of eAE in humans.

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Regulation of chaperone gene expression by heat shock transcription factor in Saccharomyces cerevisiae : Importance in normal cell growth, stress resistance, and longevity

FEBS Letters ◽

10.1016/j.febslet.2011.07.041 ◽

2011 ◽

Vol 585 (17) ◽

pp. 2744-2748 ◽

Cited By ~ 15

Author(s):

Hiroshi Sakurai ◽

Azumi Ota

Keyword(s):

Gene Expression ◽

Saccharomyces Cerevisiae ◽

Transcription Factor ◽

Heat Shock ◽

Cell Growth ◽

Stress Resistance ◽

Normal Cell ◽

Growth Stress ◽

Heat Shock Transcription Factor

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Dynamic control of Hsf1 during heat shock by a chaperone switch and phosphorylation

eLife ◽

10.7554/elife.18638 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 86

Author(s):

Xu Zheng ◽

Joanna Krakowiak ◽

Nikit Patel ◽

Ali Beyzavi ◽

Jideofor Ezike ◽

...

Keyword(s):

Mathematical Model ◽

Heat Shock ◽

Signaling Pathways ◽

Molecular Chaperones ◽

Stress Resistance ◽

Dynamic Control ◽

Protein Homeostasis ◽

Unfolded Proteins ◽

Cell Signaling Pathways ◽

Chaperone Hsp70

Heat shock factor (Hsf1) regulates the expression of molecular chaperones to maintain protein homeostasis. Despite its central role in stress resistance, disease and aging, the mechanisms that control Hsf1 activity remain unresolved. Here we show that in budding yeast, Hsf1 basally associates with the chaperone Hsp70 and this association is transiently disrupted by heat shock, providing the first evidence that a chaperone repressor directly regulates Hsf1 activity. We develop and experimentally validate a mathematical model of Hsf1 activation by heat shock in which unfolded proteins compete with Hsf1 for binding to Hsp70. Surprisingly, we find that Hsf1 phosphorylation, previously thought to be required for activation, in fact only positively tunes Hsf1 and does so without affecting Hsp70 binding. Our work reveals two uncoupled forms of regulation - an ON/OFF chaperone switch and a tunable phosphorylation gain - that allow Hsf1 to flexibly integrate signals from the proteostasis network and cell signaling pathways.

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