Heat stress reveals bidirectional cross talk between the heat shock response and UPRER in C. elegans.

Organisms rely on coordinated stress responses to maintain cellular homeostasis. Perhaps the best-known example of multiple stress inputs converging onto a single response is the integrated stress response, which reduces global translation under various stressed conditions to reduce the protein folding burden of the cell. Similarly, most stress responses generally involve coordination of additional protein homeostasis (proteostasis) pathways, including increased expression of chaperones to refold proteins, as well as activation of clearance mechanisms, such as autophagy and the ubiquitin proteasome system. Our study investigates how heat stress can influence coordinated activation of both cytosolic and endoplasmic reticulum (ER) chaperones, exploring bidirectional cross talk between canonical activators of the cytosolic heat-shock response (HSR) and the unfolded protein response of the ER (UPRER). Using robust transcriptional reporters in the Caenorhabditis elegans model system, we explore a noncanonical activation of the UPRER under heat stress by the coordinated effects of XBP-1 and HSF-1. We further investigate inter-tissue communications of stress whereby neuronal or glial activation of the UPRER can result in heterotypic enhancement of the HSR in peripheral cells and can increase thermotolerance. This work highlights the complex convergence of cellular stress responses, a phenomenon that may reflect a general strategy wherein localized stress can activate numerous proteostasis pathways to prevent whole-cell and whole-organism damage.