The disruption of COPII vesicles activates HSF-1 through SEC-23.

HSF-1 is a highly conserved transcription factor that plays a central role in protecting organisms from diverse cellular stresses. However, the mechanisms by which HSF-1 senses and responds to different types of stress remain incompletely understood. COPII-coated vesicles, responsible for transporting cargo from the endoplasmic reticulum to the Golgi apparatus, are essential for protein secretion and cellular homeostasis. Disruption of these vesicles impairs protein secretion and triggers severe proteotoxic stress. Here, we show that HSF-1 directly monitors COPII vesicle dysfunction through interactions with the core COPII component SEC-23, in both Caenorhabditis elegans and NIH3T3 cells. Inhibition of SEC-23 or SAR-1 disrupts COPII vesicle formation, leading to the release of HSF-1 from the COPII complex. This release induces a specific transcriptomic change to restore protein homeostasis. Our findings reveal a conserved mechanism by which HSF-1 responds to COPII vesicle dysregulation, providing new insights into the HSF-1-centered proteostasis network.