Guanylyl cyclase signaling in AFD neurons regulates systemic stress resilience in Caenorhabditis elegans

Thermal fluctuations in the environment, particularly high temperatures, pose a major challenge to organisms and require robust mechanisms for survival under heat stress. Although the molecular basis of cellular heat shock responses is well understood, how thermosensory neurons contribute to systemic stress adaptation remains unclear. Here, using Caenorhabditis elegans as a model, we examine whether ther-mosensory receptor guanylyl cyclases (rGCs) in AFD neurons regulate organism-wide stress responses under noxious temperatures and how individual rGCs contribute to this coordination. Among the AFD-expressed rGCs, we identify gcy-18 and gcy-23 as key regulators of the physiological response to thermal stress, acting through modulation of canonical heat shock response (HSR) genes. Our findings indicate that rGC signaling is crucial for activation of heat shock chaperones and maintenance of proteostasis under high temperatures (35 ^° C). Supporting this, quantitative analysis of HSP-16.2 revealed that rGC activity in AFD neurons modulates the HSR magnitude in distal tissues, such as the intestine. Together, our findings uncover an important role for thermosensory rGCs in maintaining cellular proteostasis through selective modulation of the HSR.