Nuclear hormone receptor NHR-49 acts in parallel with HIF-1 to promote hypoxia adaptation in <i>Caenorhabditis elegans</i>.

Abstract

The response to insufficient oxygen (hypoxia) is orchestrated by the conserved hypoxia-inducible factor (HIF). However, HIF-independent hypoxia response pathways exist that act in parallel with HIF to mediate the physiological hypoxia response. Here, we describe a hypoxia response pathway controlled by <i>Caenorhabditis elegans</i> nuclear hormone receptor NHR-49, an orthologue of mammalian peroxisome proliferator-activated receptor alpha (PPARα). We show that <i>nhr-49</i> is required for animal survival in hypoxia and is synthetic lethal with <i>hif-1</i> in this context, demonstrating that these factors act in parallel. RNA-seq analysis shows that in hypoxia <i>nhr-49</i> regulates a set of genes that are <i>hif-1-</i>independent, including autophagy genes that promote hypoxia survival. We further show that nuclear hormone receptor <i>nhr-67</i> is a negative regulator and homeodomain-interacting protein kinase <i>hpk-1</i> is a positive regulator of the NHR-49 pathway. Together, our experiments define a new, essential hypoxia response pathway that acts in parallel with the well-known HIF-mediated hypoxia response.