Fluorodeoxyuridine enhances the heat shock response and decreases polyglutamine aggregation in an HSF-1-dependent manner in Caenorhabditis elegans

AbstractThe heat shock response is the organized molecular response to stressors which disrupt proteostasis, potentially leading to protein misfolding and aggregation. While the regulation of the heat shock response is well-studied in single cells, its coordination at the cell, tissue, and systemic levels of a multicellular organism is poorly understood. To probe the interplay between systemic and cell-autonomous responses, we studied the upregulation of HSP-16.2, a molecular chaperone induced throughout the intestine of Caenorhabditis elegans following a heat shock, by taking longitudinal measurements in a microfluidic environment. Based on the dynamics of HSP-16.2 accumulation, we showed that a combination of heat shock temperature and duration define the intensity of stress inflicted on the worm and identified two regimes of low and high intensity stress. Modeling the underlying regulatory dynamics implicated the saturation of heat shock protein mRNA production in defining these two regimes and emphasized the importance of time separation between transcription and translation in establishing these dynamics. By applying a heat shock and measuring the response in separate parts of the animals, we implicated thermosensory neurons in accelerating the response and transducing information within the animal. We discuss possible implications of the systemic and cell level aspects and how they coordinate to facilitate the organismal response.

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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

Cell Stress and Chaperones ◽

10.1007/s12192-019-01064-1 ◽

2020 ◽

Vol 25 (1) ◽

pp. 173-191 ◽

Cited By ~ 7

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.

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Inhibition of Heat Shock Factor 1 (HSF1) Is More Effective At Sensitizing Myeloma Cells to Bortezomib Than Inhibition of Individual HSF1 Targets.

Blood ◽

10.1182/blood.v120.21.2953.2953 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2953-2953

Author(s):

Shardule P Shah ◽

Sagar Lonial ◽

Lawrence H. Boise

Keyword(s):

Multiple Myeloma ◽

Heat Shock ◽

Heat Shock Response ◽

Conflicts Of Interest ◽

The United States ◽

Myeloma Cell ◽

Dependent Manner ◽

Myeloma Cells ◽

Shock Response ◽

Induced Apoptosis

Abstract Abstract 2953 Multiple myeloma is a plasma cell disorder with an average incidence of 21,000 new cases per year in the United States. Recent advances in therapeutic approaches such as the use of proteasome inhibitors have resulted in a significant increase in the overall survival of myeloma patients. Myeloma cells maintain many of the characteristics of normal plasma cells, including constitutive immunoglobulin production and secretion, therefore management of ER stress plays a role in myeloma cell sensitivity to proteasome inhibition. However, myeloma cells also upregulate protective genes in response to the proteotoxic stress that can limit the therapeutic response. Previous groups have published on the importance of the heat shock response and the heat shock protein (HSP) family, supporting preclinical and clinical exploration of HSP inhibition in myeloma. Our group had interest in regulation of the HSP response and has evaluated the master regulator HSF1 as a potential therapeutic target. We found that siRNA-mediated silencing of HSF1 enhances bortezomib-induced apoptosis in a myeloma cell line. To define the effectors of the heat shock response important in regulating bortezomib response, we determined which heat shock response genes are induced by bortezomib in an HSF1-dependent manner. From a realtime PCR array of 84 HSP family genes, we found 21 genes that were induced greater than 2-fold by bortezomib. Of these 21 genes, 10 genes showed >50% reduction in HSF1-silenced cells. 7/10 genes were confirmed by independent qRT-PCR and western blot analysis. These genes include: CRYAB (alpha-crystallin B chain), DNAJB1 (HSP40 subfamily B), HSPA1A (HSP70-1A), HSPA1B (HSP70-1B), HSPB1 (HSP27), HSPH1 (HSP105/110), and HSP90AB1 (HSP90b1). To begin to determine which of these genes was important for the HSF1-dependent protective response we silenced the 7 genes individually and subsequently treated the cells with bortezomib. Surprisingly only 1 of the 7 genes silenced individually, DNAJB1, had an observable effect on bortezomib-induced death. However DNAJB1 silencing does not account for all the HSF1 activity as the increase in cell death due to bortezomib is only 48% of that observed with HSF1 silencing. Thus targeting HSF1 is more effective at sensitizing multiple myeloma cells to bortezomib-induced apoptosis than targeting individual HSPs. Moreover these data suggest that HSP90 inhibitors are functioning by inhibiting at least two members of this family to be effective as single agents. Therefore, while clinical trials for individual HSP and HSP in combination with bortezomib are being conducted, a more effective strategy for apoptosis induction is achieved through inhibition of HSP regulators such as HSF1 in combination with bortezomib. These results provide support for investigating HSP regulation in response to PI to increase the efficacy of myeloma therapy. Disclosures: No relevant conflicts of interest to declare.

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