The heat shock response and small molecule regulators

Abstract

The heat shock response (HSR) is a highly conserved cellular pathway that is responsible for stress relief and the refolding of denatured proteins [1]. When a host cell is exposed to conditions such as heat shock, ischemia, or toxic substances, heat shock factor-1 (HSF-1), a transcription factor, activates the genes that encode for the heat shock proteins (Hsps), which are a family of proteins that work alongside other chaperones to relieve stress and refold proteins that have been denatured (Burdon, 1986) [2]. Along with the refolding of denatured proteins, Hsps facilitate the removal of misfolded proteins by escorting them to degradation pathways, thereby preventing the accumulation of misfolded proteins [3]. Research has indicated that many pathological conditions, such as diabetes, cancer, neuropathy, cardiovascular disease, and aging have a negative impact on HSR function and are commonly associated with misfolded protein aggregation [4,5]. Studies indicate an interplay between mitochondrial homeostasis and HSF-1 levels can impact stress resistance, proteostasis, and malignant cell growth, which further support the role of Hsps in pathological and metabolic functions [6]. On the other hand, Hsp activation by specific small molecules can induce the heat shock response, which can afford neuroprotection and other benefits [7]. This review will focus on the modulation of Hsps and the HSR as therapeutic options to treat these conditions.

Keywords: Cancer; HSF1; Heat shock response; Hsp90; Neurodegeneration.