Abstract
BackgroundThe heat shock response (HSR) is an ancient and highly conserved program of stress-induced gene expression, aimed at reestablishing protein homeostasis to preserve cellular fitness. Cells that fail to activate or maintain this protective response are hypersensitive to proteotoxic stress. The HSR is mediated by the heat shock transcription factor 1 (HSF1), which binds to conserved heat shock elements (HSE) in the promoter region of heat shock genes, resulting in the expression of heat shock proteins (HSP). Recently, we observed that hyperactivation of RhoA conditions cardiomyocytes for the cardiac arrhythmia atrial fibrillation. Also, the HSR is annihilated in atrial fibrillation, and induction of HSR mitigates sensitization of cells to this disease. Therefore, we hypothesized active RhoA to suppress the HSR resulting in sensitization of cells for proteotoxic stimuli.Methods and ResultsStimulation of RhoA activity significantly suppressed the proteotoxic stress-induced HSR in HL-1 atrial cardiomyocytes as determined with a luciferase reporter construct driven by the HSF1 regulated human HSP70 (HSPA1A) promoter and HSP protein expression by Western Blot analysis. Inversely, RhoA inhibition boosted the proteotoxic stress-induced HSR. While active RhoA did not preclude HSF1 nuclear accumulation, phosphorylation, acetylation, or sumoylation, it did impair binding of HSF1 to the hsp genes promoter element HSE. Impaired binding results in suppression of HSP expression and sensitized cells to proteotoxic stress.ConclusionThese results reveal that active RhoA negatively regulates the HSR via attenuation of the HSF1-HSE binding and thus may play a role in sensitizing cells to proteotoxic stimuli.
Highlights
The heat shock response (HSR) is one of the main pro-survival stress responses of the cell, restoring cellular homeostasis upon exposure to proteotoxic stimuli, including heat shock, oxidative stress, heavy metal exposure, and inhibition of the proteasome [1,2,3]
Stimulation of Ras homolog gene family member A (RhoA) activity significantly suppressed the proteotoxic stress-induced HSR in HL-1 atrial cardiomyocytes as determined with a luciferase reporter construct driven by the heat shock transcription factor 1 (HSF1) regulated human HSP70 (HSPA1A) promoter and heat shock proteins (HSP) protein expression by Western Blot analysis
RhoA Abrogates the Heat Shock Response. These results reveal that active RhoA negatively regulates the HSR via attenuation of the HSF1-heat shock elements (HSE) binding and may play a role in sensitizing cells to proteotoxic stimuli
Summary
The heat shock response (HSR) is one of the main pro-survival stress responses of the cell, restoring cellular homeostasis upon exposure to proteotoxic stimuli, including heat shock, oxidative stress, heavy metal exposure, and inhibition of the proteasome [1,2,3]. Failure to mount an adequate HSR is thought to underlie hypersensitivity to acute proteotoxic stress and has been associated with disease progression in age-related chronic protein aggregation diseases, such as Huntington’s, Alzheimer’s, and Parkinson’s disease, and shortening of life-span [2,3] Atrial fibrillation represents another age-related progressive disease in which cardiac cells fail to mount an adequate HSR in response to stress caused by rapid electrical stimulation [8]. We hypothesized that RhoA signaling may negatively regulate the HSR Consistent with this hypothesis, we show that active RhoA is a suppressor of the HSR by impairing the HSF1 binding to the HSE, resulting in the inhibition of HSP expression and hyper-sensitization of cells to proteotoxic stress. We hypothesized active RhoA to suppress the HSR resulting in sensitization of cells for proteotoxic stimuli
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