Systemic activation coordinates the heat shock response of the insulin/IGF-1 pathway in Caenorhabditis elegans

Exposure to high temperatures has an adverse effect on cellular processes and results in activation of the cellular heat shock response (HSR), a highly conserved program of inducible genes to maintain protein homeostasis1. The insulin/IGF-1 signaling (IIS) pathway, which has diverse roles from metabolism to stress response and longevity, is activated as part of the HSR2–4. Recent evidence suggest that the IIS pathway is able to affect proteostasis non-autonomously5,6, yet it is not known if it is activated autonomously in stressed cells or systemically as part of an organismic program. In Caenorhabditis elegans, the single forkhead box O (FOXO) homologue DAF-16 functions as the major target of the IIS pathway7 and, together with the heat-shock factor HSF-1, induce the expression of small heat shock proteins in response to heat shock8–10,3. Here we use a novel microfluidic device that allows precise control of the spatiotemporal temperature profile to show that cellular activation of DAF-16 integrates local temperature sensation with systemic signals. We demonstrate that DAF-16 activation in head sensory neurons is essential for DAF-16 activation in other tissues, but show that no known thermosensory neuron is individually required. Our findings demonstrate that systemic and cell-autonomous aspects of stress response act together to facilitate a coordinated cellular response at the organismic level.

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Efficient Heat Shock Response Affects Hyperthermia-Induced Radiosensitization in a Tumor Spheroid Control Probability Assay

Cancers ◽

10.3390/cancers13133168 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3168

Author(s):

Oleg Chen ◽

Soňa Michlíková ◽

Lisa Eckhardt ◽

Marit Wondrak ◽

Adriana M. De Mendoza ◽

...

Keyword(s):

Stress Response ◽

Heat Shock ◽

Heat Shock Response ◽

Cellular Stress Response ◽

Proteotoxic Stress ◽

Shock Response ◽

Pre Treatment ◽

Shock Proteins ◽

The Impact

Hyperthermia (HT) combined with irradiation is a well-known concept to improve the curative potential of radiotherapy. Technological progress has opened new avenues for thermoradiotherapy, even for recurrent head and neck squamous cell carcinomas (HNSCC). Preclinical evaluation of the curative radiosensitizing potential of various HT regimens remains ethically, economically, and technically challenging. One key objective of our study was to refine an advanced 3-D assay setup for HT + RT research and treatment testing. For the first time, HT-induced radiosensitization was systematically examined in two differently radioresponsive HNSCC spheroid models using the unique in vitro “curative” analytical endpoint of spheroid control probability. We further investigated the cellular stress response mechanisms underlying the HT-related radiosensitization process with the aim to unravel the impact of HT-induced proteotoxic stress on the overall radioresponse. HT disrupted the proteome’s thermal stability, causing severe proteotoxic stress. It strongly enhanced radiation efficacy and affected paramount survival and stress response signaling networks. Transcriptomics, q-PCR, and western blotting data revealed that HT + RT co-treatment critically triggers the heat shock response (HSR). Pre-treatment with chemical chaperones intensified the radiosensitizing effect, thereby suppressing HT-induced Hsp27 expression. Our data suggest that HT-induced radiosensitization is adversely affected by the proteotoxic stress response. Hence, we propose the inhibition of particular heat shock proteins as a targeting strategy to improve the outcome of combinatorial HT + RT.

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Faculty Opinions recommendation of Regulation of the cellular heat shock response in Caenorhabditis elegans by thermosensory neurons.

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

10.3410/f.1108439.564668 ◽

2008 ◽

Author(s):

Nektarios Tavernarakis

Keyword(s):

Caenorhabditis Elegans ◽

Heat Shock ◽

Heat Shock Response ◽

Shock Response

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Urea sensitizes mIMCD3 cells to heat shock-induced apoptosis: protection by NaCl

AJP Cell Physiology ◽

10.1152/ajpcell.2001.280.3.c614 ◽

2001 ◽

Vol 280 (3) ◽

pp. C614-C620 ◽

Cited By ~ 11

Author(s):

Chantal Colmont ◽

Stéphanie Michelet ◽

Dominique Guivarc'h ◽

Germain Rousselet

Keyword(s):

Heat Shock ◽

Heat Shock Response ◽

Heat Sensitivity ◽

Osmotic Gradient ◽

Water Reabsorption ◽

Apoptotic Pathway ◽

Shock Response ◽

Induced Apoptosis ◽

Shock Proteins ◽

Dose Dependent

Urea, with NaCl, constitutes the osmotic gradient that allows water reabsorption in mammalian kidneys. Because NaCl induces heat shock proteins, we tested the responses to heat shock of mIMCD3 cells adapted to permissive urea and/or NaCl concentrations. We found that heat-induced cell death was stronger after adaptation to 250 mM urea. This effect was reversible, dose dependent, and, interestingly, blunted by 125 mM NaCl. Moreover, we have shown that urea-adapted cells engaged in an apoptotic pathway upon heat shock, as shown by DNA laddering. This sensitization is not linked to a defect in the heat shock response, because the induction of HSP70 was similar in isotonic and urea-adapted cells. Moreover, it is not linked to the presence of urea inside cells, because washing urea away did not restore heat resistance and because applying urea and heat shock at the same time did not lead to heat sensitivity. Together, these results suggest that urea modifies the heat shock response, leading to facilitated apoptosis.

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Se Alleviated Oxidative Stress-Mediated Complex Poisoning Mechanism in Pb-Treated Chicken Kidneys: Inflammation, Heat Shock Response, and Autophagy

10.21203/rs.3.rs-146251/v1 ◽

2021 ◽

Author(s):

Zhiying Miao ◽

Weikang Yu ◽

Yueyang Wang ◽

Xianhong Gu ◽

Xiaohua Teng

Keyword(s):

Oxidative Stress ◽

Heat Shock ◽

Protein Expression ◽

Heat Shock Response ◽

Potable Water ◽

Histological Structure ◽

Standard Diet ◽

Shock Response ◽

Mrna And Protein Expression ◽

Shock Proteins

Abstract Background: Lead (Pb) is a toxic environmental pollutant and can exerts toxicity in kidneys. It is known that selenium (Se) has an antagonistic effect on Pb poisoning. However, biological events during the process were not well understood in chicken kidneys.Methods: One hundred and eighty male Hyline chickens (7-day-old) were randomly divided into the control group (offering standard diet and potable water), the Se group (offering Na2SeO3-added standard diet and potable water), the Pb group (offering standard diet and (CH3OO)2Pb-added potable water), and the Pb+Se group (offering Na2SeO3-added standard diet and (CH3OO)2Pb-added potable water). On 30th, 60th, and 90th days, kidneys were removed to perform the studies of histological structure, oxidative stress indicators, cytokines, heat shock proteins, and autophagy in the chicken kidneys.Results: The experimental results indicated that Pb poisoning changed renal histological structure; decreased catalase, glutathione-s-transferase, and total antioxidative capacity activities; increased hydrogen peroxide content; induced mRNA and protein expression of heat shock proteins; inhibited interleukin (IL)-2 mRNA expression, and induced IL-4 and IL-12β mRNA expression; inhibited mammalian target of rapamycin mRNA and protein expression, and induced autophagy-related gene mRNA and protein expression in the chicken kidneys. Supplement of Se mitigated the above changes caused by Pb.Conclusion: Our research strengthens the evidence that Pb induced oxidative stress, inflammation, heat shock response, and autophagy and Se administration alleviated Pb poisoning through mitigating oxidative stress in the chicken kidneys.

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A novel assay for drug screening that utilizes the heat shock response of Caenorhabditis elegans nematodes

PLoS ONE ◽

10.1371/journal.pone.0240255 ◽

2020 ◽

Vol 15 (10) ◽

pp. e0240255

Author(s):

Chih-Hsiung Chen ◽

Rahul Patel ◽

Alessandro Bortolami ◽

Federico Sesti

Keyword(s):

Caenorhabditis Elegans ◽

Heat Shock ◽

Drug Screening ◽

Heat Shock Response ◽

Shock Response

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Activation of the heat shock response in a primary cellular model of motoneuron neurodegeneration-evidence for neuroprotective and neurotoxic effects

Cellular & Molecular Biology Letters ◽

10.2478/s11658-009-0002-8 ◽

2009 ◽

Vol 14 (2) ◽

Cited By ~ 38

Author(s):

Bernadett Kalmar ◽

Linda Greensmith

Keyword(s):

Cell Death ◽

Heat Shock ◽

Heat Shock Response ◽

Apoptotic Cell ◽

Experimental Conditions ◽

Pharmacological Agents ◽

Shock Response ◽

Induced Apoptosis ◽

Shock Proteins ◽

The Relationship

AbstractPharmacological up-regulation of heat shock proteins (hsps) rescues motoneurons from cell death in a mouse model of amyotrophic lateral sclerosis. However, the relationship between increased hsp expression and neuronal survival is not straightforward. Here we examined the effects of two pharmacological agents that induce the heat shock response via activation of HSF-1, on stressed primary motoneurons in culture. Although both arimoclomol and celastrol induced the expression of Hsp70, their effects on primary motoneurons in culture were significantly different. Whereas arimoclomol had survival-promoting effects, rescuing motoneurons from staurosporin and H2O2 induced apoptosis, celastrol not only failed to protect stressed motoneurons from apoptosis under same experimental conditions, but was neurotoxic and induced neuronal death. Immunostaining of celastrol-treated cultures for hsp70 and activated caspase-3 revealed that celastrol treatment activates both the heat shock response and the apoptotic cell death cascade. These results indicate that not all agents that activate the heat shock response will necessarily be neuroprotective.

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The Heat Shock Response and Chaperones/Heat Shock Proteins in Brain Tumors: Surface Expression, Release, and Possible Immune Consequences

Journal of Neuroscience ◽

10.1523/jneurosci.3588-07.2007 ◽

2007 ◽

Vol 27 (42) ◽

pp. 11214-11227 ◽

Cited By ~ 98

Author(s):

M. W. Graner ◽

R. I. Cumming ◽

D. D. Bigner

Keyword(s):

Heat Shock ◽

Heat Shock Proteins ◽

Brain Tumors ◽

Heat Shock Response ◽

Surface Expression ◽

Shock Response ◽

Shock Proteins

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Disruption of the three cytoskeletal networks in mammalian cells does not affect transcription, translation, or protein translocation changes induced by heat shock.

Molecular and Cellular Biology ◽

10.1128/mcb.5.7.1571 ◽

1985 ◽

Vol 5 (7) ◽

pp. 1571-1581 ◽

Cited By ~ 56

Author(s):

W J Welch ◽

J R Feramisco

Keyword(s):

Heat Shock ◽

Heat Shock Response ◽

Mammalian Cells ◽

Stress Proteins ◽

Protein Translocation ◽

Shock Response ◽

Cytochalasin E ◽

Cytoskeletal Networks ◽

Shock Proteins ◽

Cytoskeletal Elements

Mammalian cells show a complex series of transcriptional and translational switching events in response to heat shock treatment which ultimately lead to the production and accumulation of a small number of proteins, the so-called heat shock (or stress) proteins. We investigated the heat shock response in both qualitative and quantitative ways in cells that were pretreated with drugs that specifically disrupt one or more of the three major cytoskeletal networks. (These drugs alone, cytochalasin E and colcemid, do not result in induction of the heat shock response.) Our results indicated that disruption of the actin microfilaments, the vimentin-containing intermediate filaments, or the microtubules in living cells does not hinder the ability of the cell to undergo an apparently normal heat shock response. Even when all three networks were simultaneously disrupted (resulting in a loose, baglike appearance of the cells), the cells still underwent a complete heat shock response as assayed by the appearance of the heat shock proteins. In addition, the major induced 72-kilodalton heat shock protein was efficiently translocated from the cytoplasm into its proper location in the nucleus and nucleolus irrespective of the condition of the three cytoskeletal elements.

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Molecular Basis of the Defective Heat Stress Response in Mycobacterium leprae

Journal of Bacteriology ◽

10.1128/jb.00601-07 ◽

2007 ◽

Vol 189 (24) ◽

pp. 8818-8827 ◽

Cited By ~ 15

Author(s):

Diana L. Williams ◽

Tana L. Pittman ◽

Mike Deshotel ◽

Sandra Oby-Robinson ◽

Issar Smith ◽

...

Keyword(s):

Heat Stress ◽

Stress Response ◽

Heat Shock ◽

Heat Shock Response ◽

Elevated Temperatures ◽

Transcriptional Response ◽

Mycobacterium Leprae ◽

Heat Stress Response ◽

Regulatory Circuits ◽

Shock Response

ABSTRACT Mycobacterium leprae, a major human pathogen, grows poorly at 37°C. The basis for its inability to survive at elevated temperatures was investigated. We determined that M. leprae lacks a protective heat shock response as a result of the lack of transcriptional induction of the alternative sigma factor genes sigE and sigB and the major heat shock operons, HSP70 and HSP60, even though heat shock promoters and regulatory circuits for these genes appear to be intact. M. leprae sigE was found to be capable of complementing the defective heat shock response of mycobacterial sigE knockout mutants only in the presence of a functional mycobacterial sigH, which orchestrates the mycobacterial heat shock response. Since the sigH of M. leprae is a pseudogene, these data support the conclusion that a key aspect of the defective heat shock response in M. leprae is the absence of a functional sigH. In addition, 68% of the genes induced during heat shock in M. tuberculosis were shown to be either absent from the M. leprae genome or were present as pseudogenes. Among these is the hsp/acr2 gene, whose product is essential for M. tuberculosis survival during heat shock. Taken together, these results suggest that the reduced ability of M. leprae to survive at elevated temperatures results from the lack of a functional transcriptional response to heat shock and the absence of a full repertoire of heat stress response genes, including sigH.

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