Reduced Proteasome Degradation of HSF ‐1 Shifts Protein Stress Management With Age in Caenorhabditis elegans

ABSTRACT To maintain protein homeostasis, which is essential for health, animals have developed complex protective mechanisms against various acute and chronic stresses. However, the coordination of responses to these protein stresses, especially their age‐dependent changes, is not well understood. HSF‐1 is a key regulator of protein homeostasis. Our study identifies PBS‐7, a proteasome subunit, as its crucial regulator. In aged C. elegans , decreased PBS‐7 binding reduces proteasome‐mediated degradation of HSF‐1. The increase in HSF‐1 enhances responses to chronic stresses, like accumulating protein aggregates, by upregulating heat shock proteins (HSPs) and autophagy genes. Meanwhile, the upregulated HSPs suppress the activation of HSF‐1 upon acute stress, such as heat shock. Our findings reveal a mechanism that coordinates responses to acute and chronic protein stresses and highlights an adaptation prioritising protection against increasing protein aggregates in ageing.