A non-canonical role for UPR ER during heat stress in C. elegans

Abstract 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 (ISR), which reduces global translation under various stress 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 proteosome system. Our study investigates how heat stress can influence coordinated activation of both cytosolic and ER chaperones, exploring bidirectional cross talk between canonical activators of the cytosolic heat-shock response (HSR) and the unfolded protein response of the ER (UPR ER ). Using robust transcriptional reporters in the C. elegans model system, we explore a non-canonical activation of the UPR ER 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 UPR ER can result in heterotypic enhancement of the HSR in peripheral 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. Article Summary A reductionist approach to studying cellular stress responses is critical for dissecting specific molecular and genetic drivers of stress response. However, stress responses are often convergent and overlapping, and these single input and output studies may miss their complex interplay. Many studies have revealed the intricate coordination of stress responses, including the ability of seemingly organelle-specific stress responses, like mitochondrial stress responses, to directly influence cytosolic and ER health. Our study adds to this growing field by describing a unique, bidirectional crosstalk between the cytosolic and ER stress pathways, highlighting systemic coordination of stress resilience.