Tailoring of Proteostasis Networks with Heat Shock Factors

Abstract

Heat shock factors (HSFs) are the main transcriptional regulators of the heat shock response and indispensable for maintaining cellular proteostasis. HSFs mediate their protective functions through diverse genetic programs, which are composed of genes encoding molecular chaperones and other genes crucial for cell survival. The mechanisms that are used to tailor HSF-driven proteostasis networks are not yet completely understood, but they likely comprise from distinct combinations of both genetic and proteomic determinants. In this review, we highlight the versatile HSF-mediated cellular functions that extend from cellular stress responses to various physiological and pathological processes, and we underline the key advancements that have been achieved in the field of HSF research during the last decade.

Figure 1.

Domain organization of heat shock factor (HSF) family members. In mammals, six HSFs are expressed (HSF1–4, HSFX, and HSFY), which differ in their tissue expression patterns and biological functions. HSF3 is a pseudogene in humans, whereas functional HSF3 protein has been found in mouse (Mus musculus). Four HSFs have been identified in chicken (Gallus gallus). In contrast to vertebrates, a single HSF is expressed in fruit fly (Drosophila melanogaster), nematode (Caenorhabditis elegans), and yeast (Saccharomyces cerevisiae). The evolutionarily conserved DNA-binding domain (DBD) is present in all HSFs. Hydrophobic heptad repeat domain HR-A/B mediates oligomerization. Carboxy-terminal heptad repeat (HR-C) provides an intramolecular interaction site that can repress HSF oligomerization by interacting with HR-A/B. Transactivation domain (TAD) is required to enhance the transcriptional activation of certain HSFs. The mammalian HSF1 contains also a regulatory domain (RD) that is subjected to many posttranslational modifications (see Fig. 2). The numbers indicate amino acids.

Figure 2.

Heat shock factors (HSFs) undergo a selection of posttranslational modifications (PTMs) during activation and attenuation. HSF1 is phosphorylated on multiple serine (S) and threonine (T) residues, mainly located in the regulatory domain (RD). The DNA-binding domain (DBD) and the oligomerization domain (HR-A/B) harbor lysine (K) residues that are subjected to both acetylation and sumoylation. HSF1 is also ubiquitinated, but the exact ubiquitination target lysines are not known. To date, no phosphorylatable residues have been identified in HSF2. Instead, HSF2 is sumoylated at lysine residues in DBD and HR-A/B regions. Ubiquitination of five lysine residues on HSF2 have been reported. HSF4 is also subjected to phosphorylation, sumoylation, and ubiquitination. In the absence of stimulus, HSF1 is located in the cytosol in a complex that contains chaperones (HSP90, HSP70, TRiC). Steps of activation and attenuation are accompanied by a selection of PTMs. On attenuation, HSF1 is degraded by the ubiquitin-proteasome system. HR-C, carboxy-terminal heptad repeat; TAD, transactivation domain.

Figure 3.

Vertebrate heat shock factors (HSFs) are linked to a diverse array of biological processes. Although originally identified as the main factors regulating cellular responses to acute heat stress, HSFs are currently linked to an extensive array of different physiological and pathological processes. Most of the processes have been studied in the context of HSF1, and much less is currently known about the biological relevance of HSF2, HSF3, or HSF4. References for the processes that are not discussed in the main text include HSF1, ischemia (Higashi et al. 1995; Nishizawa et al. 1996); HSF1, muscle regeneration (Nishizawa et al. 2013); HSF1, acoustic injury (Sugahara et al. 2003); HSF1, immune system (Inouye et al. 2004); HSF1, viral infections (Filone et al. 2014); HSF1, circadian rhythm (Reinke et al. 2008); HSF1, oxidative stress (Ahn and Thiele 2003); HSF2, embryogenesis (Mezger et al. 1994); HSF3, cell cycle (Nakai and Ishikawa 2001); HSF3, embryogenesis (Nakai and Morimoto 1993); HSF4, oxidative stress (Liao et al. 2018); HSF4, cell cycle (Tu et al. 2006); HSF4, aging (Shi et al. 2008); and HSF1, HSF2, and HSF3, proteasomal inhibition (Kawazoe et al. 1998). The arrows depict the association between a distinct HSF family member and the process. FASD, fetal alcohol spectrum disorder.