Nuclear hormone receptor NHR-49 acts in parallel with HIF-1 to promote hypoxia adaptation in Caenorhabditis elegans
Kelsie RS Doering,
Xuanjin Cheng,
Luke Milburn,
Ramesh Ratnappan,
Arjumand Ghazi,
Dana L Miller,
Stefan Taubert
Affiliations
Kelsie RS Doering
Graduate Program in Medical Genetics, University of British Columbia, Vancouver, Canada; British Columbia Children's Hospital Research Institute, Vancouver, Canada; Centre for Molecular Medicine and Therapeutics, The University of British Columbia, Vancouver, Canada
Xuanjin Cheng
British Columbia Children's Hospital Research Institute, Vancouver, Canada; Centre for Molecular Medicine and Therapeutics, The University of British Columbia, Vancouver, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, Canada
Luke Milburn
Department of Biochemistry, University of Washington School of Medicine, Seattle, United States
Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, United States
Arjumand Ghazi
Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, United States; Departments of Developmental Biology and Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, United States
Graduate Program in Medical Genetics, University of British Columbia, Vancouver, Canada; British Columbia Children's Hospital Research Institute, Vancouver, Canada; Centre for Molecular Medicine and Therapeutics, The University of British Columbia, Vancouver, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, Canada
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 Caenorhabditis elegans nuclear hormone receptor NHR-49, an orthologue of mammalian peroxisome proliferator-activated receptor alpha (PPARα). We show that nhr-49 is required for animal survival in hypoxia and is synthetic lethal with hif-1 in this context, demonstrating that these factors act in parallel. RNA-seq analysis shows that in hypoxia nhr-49 regulates a set of genes that are hif-1-independent, including autophagy genes that promote hypoxia survival. We further show that nuclear hormone receptor nhr-67 is a negative regulator and homeodomain-interacting protein kinase hpk-1 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.
