scholarly journals Quantification of Hsp90 availability reveals differential coupling to the heat shock response

2018 ◽  
Vol 217 (11) ◽  
pp. 3809-3816 ◽  
Author(s):  
Brian D. Alford ◽  
Onn Brandman
Keyword(s):  
Heat Shock ◽  
Heat Shock Response ◽  
Protein Quality ◽  
Multiple Stressors ◽  
Stress Conditions ◽  
Proteotoxic Stress ◽  
Shock Response ◽  
Hsp90 Chaperone ◽  
Differential Coupling ◽  
Expression Program

The heat shock response (HSR) is a protective gene expression program that is activated by conditions that cause proteotoxic stress. While it has been suggested that the availability of free chaperones regulates the HSR, chaperone availability and the HSR have never been precisely quantified in tandem under stress conditions. Thus, how the availability of chaperones changes in stress conditions and the extent to which these changes drive the HSR are unknown. In this study, we quantified Hsp90 chaperone availability and the HSR under multiple stressors. We show that Hsp90-dependent and -independent pathways both regulate the HSR, and the contribution of each pathway varies greatly depending on the stressor. Moreover, stressors that regulate the HSR independently of Hsp90 availability do so through the Hsp70 chaperone. Thus, the HSR responds to diverse defects in protein quality by monitoring the state of multiple chaperone systems independently.

scholarly journals Sis1 delivers the State of the Union

2020 ◽  
Vol 220 (1) ◽  
Author(s):  
Danish Khan ◽  
Onn Brandman
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Heat Shock ◽  
Heat Shock Response ◽  
The State ◽  
Gene Expression Program ◽  
State Of The Union ◽  
Shock Response ◽  
Expression Program

The heat shock response (HSR) is a gene expression program that protects cells from heat and proteotoxic stressors. In this issue, Feder et al. (2020. J. Cell Biol.https://doi.org/10.1083/jcb.202005165) show that subcellular relocalization of the cochaperone Sis1 drives the HSR by de-suppressing the transcription factor Hsf1.

scholarly journals The Quinone Methide Aurin Is a Heat Shock Response Inducer That Causes Proteotoxic Stress and Noxa-dependent Apoptosis in Malignant Melanoma Cells

2014 ◽  
Vol 290 (3) ◽  
pp. 1623-1638 ◽  
Author(s):  
Angela L. Davis ◽  
Shuxi Qiao ◽  
Jessica L. Lesson ◽  
Montserrat Rojo de la Vega ◽  
Sophia L. Park ◽  
...  
Keyword(s):  
Heat Shock ◽  
Malignant Melanoma ◽  
Heat Shock Response ◽  
Melanoma Cells ◽  
Quinone Methide ◽  
Proteotoxic Stress ◽  
Shock Response

scholarly journals Depending on the stress, histone deacetylase inhibitors act as heat shock protein co-inducers in motor neurons and potentiate arimoclomol, exerting neuroprotection through multiple mechanisms in ALS models

2020 ◽  
Vol 25 (1) ◽  
pp. 173-191 ◽  
Author(s):  
Rachel Kuta ◽  
Nancy Larochelle ◽  
Mario Fernandez ◽  
Arun Pal ◽  
Sandra Minotti ◽  
...  
Keyword(s):  
Heat Shock ◽  
Histone Deacetylase ◽  
Motor Neurons ◽  
Heat Shock Response ◽  
Hdac Inhibitors ◽  
Dependent Manner ◽  
Hdac Inhibition ◽  
Proteotoxic Stress ◽  
Shock Response ◽  
Stress Dependent

AbstractUpregulation of heat shock proteins (HSPs) is an approach to treatment of neurodegenerative disorders with impaired proteostasis. Many neurons, including motor neurons affected in amyotrophic lateral sclerosis (ALS), are relatively resistant to stress-induced upregulation of HSPs. This study demonstrated that histone deacetylase (HDAC) inhibitors enable the heat shock response in cultured spinal motor neurons, in a stress-dependent manner, and can improve the efficacy of HSP-inducing drugs in murine spinal cord cultures subjected to thermal or proteotoxic stress. The effect of particular HDAC inhibitors differed with the stress paradigm. The HDAC6 (class IIb) inhibitor, tubastatin A, acted as a co-inducer of Hsp70 (HSPA1A) expression with heat shock, but not with proteotoxic stress induced by expression of mutant SOD1 linked to familial ALS. Certain HDAC class I inhibitors (the pan inhibitor, SAHA, or the HDAC1/3 inhibitor, RGFP109) were HSP co-inducers comparable to the hydroxyamine arimoclomol in response to proteotoxic stress, but not thermal stress. Regardless, stress-induced Hsp70 expression could be enhanced by combining an HDAC inhibitor with either arimoclomol or with an HSP90 inhibitor that constitutively induced HSPs. HDAC inhibition failed to induce Hsp70 in motor neurons expressing ALS-linked mutant FUS, in which the heat shock response was suppressed; yet SAHA, RGFP109, and arimoclomol did reduce loss of nuclear FUS, a disease hallmark, and HDAC inhibition rescued the DNA repair response in iPSC-derived motor neurons carrying the FUSP525Lmutation, pointing to multiple mechanisms of neuroprotection by both HDAC inhibiting drugs and arimoclomol.

scholarly journals Subcellular localization of the J-protein Sis1 regulates the heat shock response

2020 ◽  
Vol 220 (1) ◽  
Author(s):  
Zoë A. Feder ◽  
Asif Ali ◽  
Abhyudai Singh ◽  
Joanna Krakowiak ◽  
Xu Zheng ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Response ◽  
Spatial Organization ◽  
Protein Homeostasis ◽  
Shock Response ◽  
Conserved Gene ◽  
Encoding Protein ◽  
Expression Program ◽  
The Relationship ◽  
J Protein

Cells exposed to heat shock induce a conserved gene expression program, the heat shock response (HSR), encoding protein homeostasis (proteostasis) factors. Heat shock also triggers proteostasis factors to form subcellular quality control bodies, but the relationship between these spatial structures and the HSR is unclear. Here we show that localization of the J-protein Sis1, a cofactor for the chaperone Hsp70, controls HSR activation in yeast. Under nonstress conditions, Sis1 is concentrated in the nucleoplasm, where it promotes Hsp70 binding to the transcription factor Hsf1, repressing the HSR. Upon heat shock, Sis1 forms an interconnected network with other proteostasis factors that spans the nucleolus and the surface of the endoplasmic reticulum. We propose that localization of Sis1 to this network directs Hsp70 activity away from Hsf1 in the nucleoplasm, leaving Hsf1 free to induce the HSR. In this manner, Sis1 couples HSR activation to the spatial organization of the proteostasis network.

scholarly journals Proteotoxic stress of cancer: Implication of the heat-shock response in oncogenesis

2012 ◽  
Vol 227 (8) ◽  
pp. 2982-2987 ◽  
Author(s):  
Chengkai Dai ◽  
Siyuan Dai ◽  
Junyue Cao
Keyword(s):  
Heat Shock ◽  
Heat Shock Response ◽  
Proteotoxic Stress ◽  
Shock Response

scholarly journals Subcellular localization of the J-protein Sis1 regulates the heat shock response

2020 ◽  
Author(s):  
Zoe A. Feder ◽  
Asif Ali ◽  
Abhyudai Singh ◽  
Joanna Krakowiak ◽  
Xu Zheng ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Response ◽  
Spatial Organization ◽  
Protein Homeostasis ◽  
Spatial Structures ◽  
Shock Response ◽  
Conserved Gene ◽  
Expression Program ◽  
The Relationship ◽  
J Protein

ABSTRACTCells exposed to heat shock induce a conserved gene expression program – the heat shock response (HSR) – encoding chaperones like Hsp70 and other protein homeostasis (proteostasis) factors. Heat shock also triggers proteostasis factors to form subcellular quality control bodies, but the relationship between these spatial structures and the HSR is unclear. Here we show that localization of the J-protein Sis1 – a co-chaperone for Hsp70 – controls HSR activation in yeast. Under nonstress conditions, Sis1 is concentrated in the nucleoplasm where it promotes Hsp70 binding to the transcription factor Hsf1, repressing the HSR. Upon heat shock, Sis1 forms an interconnected network with other proteostasis factors that spans the nucleolus and the surface of the cortical ER. We propose that localization of Sis1 to this network directs Hsp70 activity away from Hsf1 in the nucleoplasm, leaving Hsf1 free to induce the HSR. In this manner, Sis1 couples HSR activation to the spatial organization of the proteostasis network.One sentence summaryLocalization of the J-protein Sis1 to a subcellular network of proteostasis factors activates the heat shock response.

scholarly journals The amino acid substitution affects cellular response to mistranslation

2021 ◽  
Author(s):  
Matthew D. Berg ◽  
Yanrui Zhu ◽  
Bianca Y. Ruiz ◽  
Raphaël Loll-Krippleber ◽  
Joshua Isaacson ◽  
...  
Keyword(s):  
Amino Acid ◽  
Heat Shock ◽  
Amino Acid Substitution ◽  
Heat Shock Response ◽  
Cellular Response ◽  
Genetic Interactions ◽  
Similar Frequency ◽  
Proteotoxic Stress ◽  
Shock Response ◽  
The Impact

Mistranslation, the mis-incorporation of an amino acid not specified by the standard genetic code, occurs in all organisms. tRNA variants that increase mistranslation arise spontaneously and engineered tRNAs can achieve mistranslation frequencies approaching 10% in yeast and bacteria. Interestingly, human genomes contain tRNA variants with the potential to mistranslate. Cells cope with increased mistranslation through multiple mechanisms, though high levels cause proteotoxic stress. The goal of this study was to compare the genetic interactions and the impact on transcriptome and cellular growth of two tRNA variants that mistranslate at a similar frequency but create different amino acid substitutions in Saccharomyces cerevisiae. One tRNA variant inserts alanine at proline codons whereas the other inserts serine for arginine. Both tRNAs decreased growth rate, with the effect being greater for arginine to serine than for proline to alanine. The tRNA that substituted serine for arginine resulted in a heat shock response. In contrast, heat shock response was minimal for proline to alanine substitution. Further demonstrating the significance of the amino acid substitution, transcriptome analysis identified unique up- and downregulated genes in response to each mistranslating tRNA. Number and extent of negative synthetic genetic interactions also differed depending upon type of mistranslation. Based on the unique responses observed for these mistranslating tRNAs, we predict that the potential of mistranslation to exacerbate diseases caused by proteotoxic stress depends on the tRNA variant. Furthermore, based on their unique transcriptomes and genetic interactions, different naturally occurring mistranslating tRNAs have the potential to negatively influence specific diseases.

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