scholarly journals Neuronal HSF-1 coordinates the propagation of fat desaturation across tissues to enable adaptation to high temperatures in C. elegans

PLoS Biology ◽  
2021 ◽  
Vol 19 (11) ◽  
pp. e3001431
Author(s):  
Laetitia Chauve ◽  
Francesca Hodge ◽  
Sharlene Murdoch ◽  
Fatemah Masoudzadeh ◽  
Harry-Jack Mann ◽  
...  
Keyword(s):  
Heat Shock ◽  
Elevated Temperatures ◽  
Transforming Growth Factor ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Fine Tuning ◽  
Heat Shock Factor 1 ◽  
Adaptive Responses ◽  
Peripheral Tissues ◽  
C Elegans

To survive elevated temperatures, ectotherms adjust the fluidity of membranes by fine-tuning lipid desaturation levels in a process previously described to be cell autonomous. We have discovered that, in Caenorhabditis elegans, neuronal heat shock factor 1 (HSF-1), the conserved master regulator of the heat shock response (HSR), causes extensive fat remodeling in peripheral tissues. These changes include a decrease in fat desaturase and acid lipase expression in the intestine and a global shift in the saturation levels of plasma membrane’s phospholipids. The observed remodeling of plasma membrane is in line with ectothermic adaptive responses and gives worms a cumulative advantage to warm temperatures. We have determined that at least 6 TAX-2/TAX-4 cyclic guanosine monophosphate (cGMP) gated channel expressing sensory neurons, and transforming growth factor ß (TGF-β)/bone morphogenetic protein (BMP) are required for signaling across tissues to modulate fat desaturation. We also find neuronal hsf-1 is not only sufficient but also partially necessary to control the fat remodeling response and for survival at warm temperatures. This is the first study to show that a thermostat-based mechanism can cell nonautonomously coordinate membrane saturation and composition across tissues in a multicellular animal.

scholarly journals Remodeling of the C. elegans Non-coding RNA Transcriptome by Heat Shock

2019 ◽  
Author(s):  
William P. Schreiner ◽  
Delaney C. Pagliuso ◽  
Jacob M. Garrigues ◽  
Jerry S. Chen ◽  
Antti P. Aalto ◽  
...  
Keyword(s):  
Heat Shock ◽  
Elevated Temperatures ◽  
Transcriptional Response ◽  
Heat Shock Factor 1 ◽  
Protein Coding ◽  
Repeat Elements ◽  
Cellular Survival ◽  
C Elegans ◽  
Non Coding Rna ◽  
Shock Proteins

ABSTRACTElevated temperatures activate a Heat Shock Response (HSR) to protect cells from the pathological effects of protein mis-folding, cellular mis-organization, organelle dysfunction and altered membrane fluidity. This response includes activation of the conserved transcription factor Heat Shock Factor 1 (HSF-1), which binds Heat Shock Elements (HSEs) in the promoters of genes induced by heat shock (HS). The up-regulation of protein-coding genes (PCGs), such as Heat Shock Proteins (HSPs) and cytoskeletal regulators, is critical for cellular survival during elevated temperatures. While the transcriptional response of PCGs to heat shock has been comprehensively analyzed in a variety of organisms, the effect of this stress on the expression of non-coding RNAs (ncRNAs) has not been systematically examined. Here we show that in Caenorhabditis elegans HS induces up- and down-regulation of specific ncRNAs from multiple classes, including miRNA, piRNA, lincRNA, pseudogene, and repeat elements. Moreover, some ncRNA genes appear to be direct targets of the HSR, as they contain HSF-1 bound HSEs in their promoters and their expression is regulated by this factor during HS. These results demonstrate that multiple ncRNA genes respond to HS, some as direct HSF-1 targets, providing new candidates that may contribute to organismal survival during this stress.

scholarly journals Remodeling of the Caenorhabditis elegans non-coding RNA transcriptome by heat shock

2019 ◽  
Vol 47 (18) ◽  
pp. 9829-9841 ◽  
Author(s):  
William P Schreiner ◽  
Delaney C Pagliuso ◽  
Jacob M Garrigues ◽  
Jerry S Chen ◽  
Antti P Aalto ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Heat Shock ◽  
Elevated Temperatures ◽  
Transcriptional Response ◽  
Heat Shock Factor 1 ◽  
Protein Coding ◽  
Repeat Elements ◽  
Cellular Survival ◽  
Non Coding Rna ◽  
Shock Proteins

Abstract Elevated temperatures activate a heat shock response (HSR) to protect cells from the pathological effects of protein mis-folding, cellular mis-organization, organelle dysfunction and altered membrane fluidity. This response includes activation of the conserved transcription factor heat shock factor 1 (HSF-1), which binds heat shock elements (HSEs) in the promoters of genes induced by heat shock (HS). The upregulation of protein-coding genes (PCGs), such as heat shock proteins and cytoskeletal regulators, is critical for cellular survival during elevated temperatures. While the transcriptional response of PCGs to HS has been comprehensively analyzed in a variety of organisms, the effect of this stress on the expression of non-coding RNAs (ncRNAs) has not been systematically examined. Here we show that in Caenorhabditis elegans HS induces up- and downregulation of specific ncRNAs from multiple classes, including miRNA, piRNA, lincRNA, pseudogene and repeat elements. Moreover, some ncRNA genes appear to be direct targets of the HSR, as they contain HSF-1 bound HSEs in their promoters and their expression is regulated by this factor during HS. These results demonstrate that multiple ncRNA genes respond to HS, some as direct HSF-1 targets, providing new candidates that may contribute to organismal survival during this stress.

Protein kinases G are essential downstream mediators of the antifibrotic effects of sGC stimulators

2018 ◽  
Vol 77 (3) ◽  
pp. 459-459 ◽  
Author(s):  
Alexandru-Emil Matei ◽  
Christian Beyer ◽  
Andrea-Hermina Györfi ◽  
Alina Soare ◽  
Chih-Wei Chen ◽  
...  
Keyword(s):  
Protein Kinases ◽  
Transforming Growth Factor ◽  
Soluble Guanylate Cyclase ◽  
Cyclic Guanosine Monophosphate ◽  
Transforming Growth Factor Β1 ◽  
Guanosine Monophosphate ◽  
Dependent Manner ◽  
Erk Phosphorylation ◽  
Sgc Stimulators

ObjectivesStimulators of soluble guanylate cyclase (sGC) are currently investigated in clinical trials for the treatment of fibrosis in systemic sclerosis (SSc). In this study, we aim to investigate the role of protein kinases G (PKG) as downstream mediators of sGC–cyclic guanosine monophosphate (cGMP) in SSc.MethodsMice with combined knockout of PKG1 and 2 were challenged with bleomycin and treated with the sGC stimulator BAY 41-2272. Fibroblasts were treated with BAY 41-2272 and with the PKG inhibitor KT 5823.ResultsPKG1 and 2 are upregulated in SSc in a transforming growth factor-β1 (TGFβ1)-dependent manner, as an attempt to compensate for the decreased signalling through the sGC–cGMP–PKG pathway. Inhibition or knockout of PKG1 and 2 abrogates the inhibitory effects of sGC stimulation on fibroblast activation in a SMAD-independent, but extracellular signal-regulated kinase (ERK)-dependent manner. In vivo, sGC stimulation fails to prevent bleomycin-induced fibrosis in PKG1 and 2 knockout mice.ConclusionsOur data provide evidence that PKGs are essential mediators of the antifibrotic effects of sGC stimulators through interfering with non-canonical TGFβ signalling. TGFβ1 promotes its profibrotic effects through inhibition of sGC–cGMP–PKG signalling, sGC stimulation exerts its antifibrotic effects by inhibition of TGFβ1-induced ERK phosphorylation.

scholarly journals Differential Regulation of the Heat Shock Factor 1 and DAF-16 by Neuronal nhl-1 in the Nematode C. elegans

Cell Reports ◽  
2014 ◽  
Vol 9 (6) ◽  
pp. 2192-2205 ◽  
Author(s):  
Yuli Volovik ◽  
Lorna Moll ◽  
Filipa Carvalhal Marques ◽  
Moria Maman ◽  
Michal Bejerano-Sagie ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Factor ◽  
Differential Regulation ◽  
Heat Shock Factor 1 ◽  
C Elegans

scholarly journals Diversification of the Caenorhabditis heat shock response by Helitron transposable elements

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Jacob M Garrigues ◽  
Brian V Tsu ◽  
Matthew D Daugherty ◽  
Amy E Pasquinelli
Keyword(s):  
Heat Shock ◽  
Rna Polymerase Ii ◽  
Heat Shock Response ◽  
Heat Shock Factor 1 ◽  
Cellular Protection ◽  
C Elegans ◽  
Expression Of Genes ◽  
Shock Response ◽  
Caenorhabditis Species ◽  
Species Specific

Heat Shock Factor 1 (HSF-1) is a key regulator of the heat shock response (HSR). Upon heat shock, HSF-1 binds well-conserved motifs, called Heat Shock Elements (HSEs), and drives expression of genes important for cellular protection during this stress. Remarkably, we found that substantial numbers of HSEs in multiple Caenorhabditis species reside within Helitrons, a type of DNA transposon. Consistent with Helitron-embedded HSEs being functional, upon heat shock they display increased HSF-1 and RNA polymerase II occupancy and up-regulation of nearby genes in C. elegans. Interestingly, we found that different genes appear to be incorporated into the HSR by species-specific Helitron insertions in C. elegans and C. briggsae and by strain-specific insertions among different wild isolates of C. elegans. Our studies uncover previously unidentified targets of HSF-1 and show that Helitron insertions are responsible for rewiring and diversifying the Caenorhabditis HSR.

scholarly journals BAY 41-2272 Attenuates CTGF Expression via sGC/cGMP-Independent Pathway in TGFβ1-Activated Hepatic Stellate Cells

Biomedicines ◽  
2020 ◽  
Vol 8 (9) ◽  
pp. 330
Author(s):  
Po-Jen Chen ◽  
Liang-Mou Kuo ◽  
Yi-Hsiu Wu ◽  
Yu-Chia Chang ◽  
Kuei-Hung Lai ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatic Stellate Cells ◽  
Transforming Growth Factor ◽  
Soluble Guanylyl Cyclase ◽  
Stellate Cells ◽  
Cyclic Guanosine Monophosphate ◽  
Tissue Growth ◽  
Guanosine Monophosphate ◽  
Fibrotic Disorders ◽  
The Impact

Activation of hepatic stellate cells (HSCs) is a critical pathogenic feature of liver fibrosis and cirrhosis. BAY 41-2272 is a canonical non-nitric oxide (NO)-based soluble guanylyl cyclase (sGC) stimulator that triggers cyclic guanosine monophosphate (cGMP) signaling for attenuation of fibrotic disorders; however, the impact of BAY 41-2272 on HSC activation remains ill-defined. Transforming growth factor (TGF)β and its downstream connective tissue growth factor (CTGF or cellular communication network factor 2, CCN2) are critical fibrogenic cytokines for accelerating HSC activation. Here, we identified that BAY 41-2272 significantly inhibited the TGFβ1-induced mRNA and protein expression of CTGF in mouse primary HSCs. Indeed, BAY 41-2272 increased the sGC activity and cGMP levels that were potentiated by two NO donors and inhibited by a specific sGC inhibitor, ODQ. Surprisingly, the inhibitory effects of BAY 41-2272 on CTGF expression were independent of the sGC/cGMP pathway in TGFβ1-activated primary HSCs. BAY 41-2272 selectively restricted the TGFβ1-induced phosphorylation of Akt but not canonical Smad2/3 in primary HSCs. Together, we illustrate a unique framework of BAY 41-2272 for inhibiting TGFβ1-induced CTGF upregulation and HSC activation via a noncanonical Akt-dependent but sGC/cGMP-independent pathway.

scholarly journals Dual Pharmacological Targeting of HDACs and PDE5 Inhibits Liver Disease Progression in a Mouse Model of Biliary Inflammation and Fibrosis

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3748
Author(s):  
Alex Claveria-Cabello ◽  
Leticia Colyn ◽  
Iker Uriarte ◽  
Maria Ujue Latasa ◽  
Maria Arechederra ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Fibrosis ◽  
Single Molecule ◽  
Histone Deacetylases ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Pde5 Inhibitor ◽  
Transforming Growth Factor Β ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate

Liver fibrosis, a common hallmark of chronic liver disease (CLD), is characterized by the accumulation of extracellular matrix secreted by activated hepatic fibroblasts and stellate cells (HSC). Fibrogenesis involves multiple cellular and molecular processes and is intimately linked to chronic hepatic inflammation. Importantly, it has been shown to promote the loss of liver function and liver carcinogenesis. No effective therapies for liver fibrosis are currently available. We examined the anti-fibrogenic potential of a new drug (CM414) that simultaneously inhibits histone deacetylases (HDACs), more precisely HDAC1, 2, and 3 (Class I) and HDAC6 (Class II) and stimulates the cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway activity through phosphodiesterase 5 (PDE5) inhibition, two mechanisms independently involved in liver fibrosis. To this end, we treated Mdr2-KO mice, a clinically relevant model of liver inflammation and fibrosis, with our dual HDAC/PDE5 inhibitor CM414. We observed a decrease in the expression of fibrogenic markers and collagen deposition, together with a marked reduction in inflammation. No signs of hepatic or systemic toxicity were recorded. Mechanistic studies in cultured human HSC and cholangiocytes (LX2 and H69 cell lines, respectively) demonstrated that CM414 inhibited pro-fibrogenic and inflammatory responses, including those triggered by transforming growth factor β (TGFβ). Our study supports the notion that simultaneous targeting of pro-inflammatory and fibrogenic mechanisms controlled by HDACs and PDE5 with a single molecule, such as CM414, can be a new disease-modifying strategy.

scholarly journals Inhibition of hypoxia-inducible factor 1α accumulation by glyceryl trinitrate and cyclic guanosine monophosphate

2020 ◽  
Vol 40 (1) ◽  
Author(s):  
Judy Kim ◽  
Ivraym B. Barsoum ◽  
Harrison Loh ◽  
Jean-François Paré ◽  
D. Robert Siemens ◽  
...  
Keyword(s):  
Glyceryl Trinitrate ◽  
Hypoxia Inducible Factor ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Protein Accumulation ◽  
Dependent Manner ◽  
Adaptive Responses ◽  
Calpain Activity ◽  
Hypoxia Inducible Factor 1 ◽  
Cgmp Signalling

Abstract A key mechanism mediating cellular adaptive responses to hypoxia involves the activity of hypoxia-inducible factor 1 (HIF-1), a transcription factor composed of HIF-1α, and HIF-1β subunits. The classical mechanism of regulation of HIF-1 activity involves destabilisation of HIF-1α via oxygen-dependent hydroxylation of proline residues and subsequent proteasomal degradation. Studies from our laboratory revealed that nitric oxide (NO)-mediated activation of cyclic guanosine monophosphate (cGMP) signalling inhibits the acquisition of hypoxia-induced malignant phenotypes in tumour cells. The present study aimed to elucidate a mechanism of HIF-1 regulation involving NO/cGMP signalling. Using human DU145 prostate cancer cells, we assessed the effect of the NO mimetic glyceryl trinitrate (GTN) and the cGMP analogue 8-Bromo-cGMP on hypoxic accumulation of HIF-1α. Concentrations of GTN known to primarily activate the NO/cGMP pathway (100 nM–1 µM) inhibited hypoxia-induced HIF-1α protein accumulation in a time-dependent manner. Incubation with 8-Bromo-cGMP (1 nM–10 µM) also attenuated HIF-1α accumulation, while levels of HIF-1α mRNA remained unaltered by exposure to GTN or 8-Bromo-cGMP. Furthermore, treatment of cells with the calpain (Ca2+-activated proteinase) inhibitor calpastatin attenuated the effects of GTN and 8-Bromo-cGMP on HIF-1α accumulation. However, since calpain activity was not affected by incubation of DU145 cells with various concentrations of GTN or 8-Bromo-cGMP (10 nM or 1 µM) under hypoxic or well-oxygenated conditions, it is unlikely that NO/cGMP signalling inhibits HIF-1α accumulation via regulation of calpain activity. These findings provide evidence for a role of NO/cGMP signalling in the regulation of HIF-1α, and hence HIF-1-mediated hypoxic responses, via a mechanism dependent on calpain.

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