The heat shock factor code: Specifying a diversity of transcriptional regulatory programs broadly promoting stress resilience

Abstract

The heat shock factor (HSF) family of transcription factors drives gene expression programs that maintain cytosolic protein homeostasis (proteostasis) in response to a vast array of physiological and exogenous stressors. The importance of HSF function has been demonstrated in numerous physiological and pathological contexts. Evidence accumulating over the last two decades has revealed that the regulatory programs driven by the HSF family can vary dramatically depending on the context in which it is activated. To broadly maintain proteostasis across these contexts, HSFs must bind and appropriately regulate the correct target genes at the correct time. Here, we discuss "the heat shock factor code"-our current understanding of how human cells use HSF paralog diversification and interplay, local concentration, post-translational modifications, and interactions with other proteins to enable the functional plasticity required for cellular resilience across a multitude of environments.

Keywords: HSF1; HSF2; HSF4; Post-translation modification; Transcriptional regulation.

Fig. 1

The heat shock factor (HSF) code: oligomerization, local protein concentration, post-translational modifications (PTMs), and protein–protein interactions of human HSFs enable functional diversity required for cellular resilience.

Fig. 2

The role of post-translational modifications on the function of HSFs. Post-translational modifications, including phosphorylation, acetylation, and sumoylation, are indicated on HSF1, HSF2, and HSF4. These PTMs alter HSFs DNA-binding, stability, activation, as well as protein–protein interactions. HSF, heat shock factor; PTM, post-translational modification.

Fig. 3

The protein–protein interaction (PPI) network of HSFs. This network illustrates key PPIs for HSF1, HSF2, and HSF4 from validated coimmunoprecipitation studies and affinity capture-mass spectrometry/affinity-captured luminescence studies derived from the BioGRID database. Nodes represent individual proteins, and edges represent interactions between proteins. HSF1, HSF2, and HSF4 are shown as central hubs, with distinct and shared interactors highlighted. HSF-interacting proteins that have been shown to promote or suppress HSF1 stability or activity are highlighted. HSF, heat shock factor.