More than the 'master regulator of cytosolic proteostasis': new roles for HSF1 in promoting tissue health.

Maintaining protein homeostasis (proteostasis) is crucial for long-term tissue health. This requires the action of stress response pathways and protein quality control mechanisms that act within or across different sub-cellular compartments to preserve proteome integrity. Within the cytosol/nucleus, the loss of proteostasis induces a transcriptional programme known as the heat-shock response (HSR) through activation of heat-shock factor 1 (HSF1). The HSR rapidly elevates levels of molecular chaperones, co-chaperones and protein degradation factors that restore proteostasis in the cytosol/nucleus. As a result, the ability of HSF1 to promote tissue health has long been attributed to its capacity to safeguard the cytosolic/nucleosolic proteome. However, over the past 15 years, it has become apparent that HSF1 activity is also intimately coupled with the biogenesis and maintenance of other organelles, including mitochondria, peroxisomes, the endoplasmic reticulum, lysosomes and chloroplasts. This suggests that HSF1 promotes tissue health in plants and animals through mechanisms beyond the maintenance of cytosolic/nucleosolic proteostasis. In this opinion piece, I will discuss advances in our understanding of the interplay between HSF1 and organelle homeostasis and make the case that the existing model for the relationship between HSF1 and tissue health should be expanded to encompass these additional roles. This article is part of the Theo Murphy meeting issue 'ProteostaSys: a systems view of proteostasis'.