Phosphatidylcholine Mediates The Crosstalk Between Let-607 And Daf-16 Stress Response Pathways

Coordinated regulation of stress response pathways is crucial for cellular homeostasis. However, crosstalk between the different stress pathways and the physiological significance of this crosstalk remain poorly understood. In this study, using the model organism C. elegans, we discovered that suppression of the transcription factor LET-607/CREBH, a regulator of cellular defense and proteostatic responses, triggers adaptive induction of DAF-16-dependent stress responses. Suppression of LET-607 improves stress resistance and extends C. elegans lifespan in a DAF-16-dependent manner. We identified the sphingomyelin synthase SMS-5 to be a central mediator in the communication between LET-607 and DAF-16. SMS-5 reduces the contents of unsaturated phosphatidylcholine (PC), which activates DAF-16 through ITR-1-dependent calcium signaling and calcium-sensitive kinase PKC-2. Our data reveal the significance of crosstalk between different stress pathways in animal fitness and identify LET-607/CREBH and specific PC as regulators of DAF-16 and longevity.Author summary In order to cope with stresses, cells have evolved complex and elegant adaptive mechanisms, which are also referred to as stress responses. Central to these responses are core transcription factors. It is widely hypothesized that interruption of one key stress response pathway could compromise overall cellular function and survival. In order to avoid such an issue, stress response pathways communicate with each other. A defect in one pathway may adaptively activate other pathways, thus restoring homeostasis and increasing fitness. However, how these pathways communicate is largely unexplored. In this study, we unraveled crosstalk between the LET-607 and DAF-16 pathways in C. elegans. Suppression of LET-607, a regulator of defense and proteostatic responses, was shown to adaptively activate DAF-16, which is a crucial regulator of general stress responses. This crosstalk was shown to be vital for animal fitness, as suppression of LET-607 extends lifespan in a DAF-16-dependent manner. Intriguingly, loss of LET-607 results in increased levels of the sphingomyelin synthase SMS-5, which metabolizes membrane lipid PC. Consequently, the reduction in PC causes activation of DAF-16 via membrane-located calcium channel ITR-1 and calcium-sensitive kinase PKC-2. This study identifies a novel crosstalk between stress response pathways, which is potentially significant in animal longevity.