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

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.