Genes that link the insulin/IGF-like signaling pathway to stress response

The insulin/IGF-like signaling cascade and stress response pathways are conserved throughout the animal kingdom and known to modulate a wide-range of biological processes to cope with environmental cues or stress. Previous studies have suggested that the insulin/IGF-like signaling and stress response are functionally linked and may play an integral role in controlling aging and longevity. However, our understanding regarding the underlying molecular mechanisms of the cross-talks between the insulin/IGF-like signaling and stress response pathways are incomplete. Thus, in this study, we aimed to further elucidate the cross-talks between these evolutionally conserved biological pathways by studying novel regulators of these pathways. We demonstrated two potential mechanisms that mediate the cross-talk between insulin/IGF-like signaling and stress response. (1) We found that the activity of HSF-1 is regulated by insulin/IGF-like signaling pathway via two novel HSF-1 regulators, DDL-1 and DDL-2. DDL-1 and -2 negatively regulate HSF-1 activity by forming a protein complex with HSF-1, and the formation of this complex (DHIC) is modulated by the activity of insulin/IGF-like signaling. These data suggested a role for DDL-1 and DDL-2 in insulin/IGF-like signaling-mediated HSF-1 regulation. (2) We also demonstrated that C. elegans SIR-2.4 is required for the cellular responses to multiple stressors and promotes stress-induced DAF-16 (FoxO transcription factor) activation. Although SIR-2.4 is a member of the sirtuin deacetylase family, the catalytic activity of SIR-2.4 is dispensable for modulating DAF-16 nuclear translocation. We found that SIR-2.4 regulates DAF-16 function by preventing CBP-1-mediated acetylation, possibly via protein-protein interaction. Overall, our work presented in this study has provided a broader understanding of potential mechanisms that the link insulin/IGF-like signaling pathway and stress response together at the molecular level.