Genetic Dissection Reveals New Components of the NHR-49 Multi-Stress Resistance and Longevity Pathway

Cells, tissues, and organisms encounter many environmental and endogenous stresses, and the ability to mount specific responses to these stresses is critical to achieve homeostasis and survival.Stress also occurs in many pathological states and is therefore of great biomedical relevance, both as a cause or contributor to diseases and as a potential therapeutic target.Pathways that regulate the responses to oxidative stress, hypoxia, and starvation are evolutionarily conserved from the nematode Caenorhabditis elegans to humans and involve master regulators of gene expression.One such stress response pathway engages C. elegans NHR-49, an orthologue of mammalian PPAR, which is required to survive tBOOH-induced oxidative stress, hypoxia, and starvation, and is also a key effector in many genetic longevity pathways.However, in contrast to other stress response pathways such as SKN-1/Nrf2 and HIF-1/HIF signaling, many aspects of NHR-49 signaling remain poorly understood.To map new components of this pathway, we performed reverse genetic screens, uncovering 80 candidate kinases, transcription factors, and transcriptional coregulators required for NHR-49-controlled gene activation in tBOOH, hypoxia, and/or starvation.Further analysis revealed that the kinase hpk-1/HIPK is required in the nhr-49 pathway for hypoxia and oxidative stress survival, that pseudokinase nipi-3 is required with nhr-49 for hypoxia survival, and that transcription factor nhr-80 is required with nhr-49 for hypoxia and oxidative stress survival and for the normal lifespan of wild-type C. elegans.Collectively, our data identify numerous new potential regulators in an important stress response and thus substantially enhance our understanding of stress adaptation and longevity regulation.