期刊
ELIFE
卷 11, 期 -, 页码 -出版社
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.67911
关键词
hypoxia; gene expression; transcription factors; nuclear receptor; HIF; autophagy; C; elegans
类别
资金
- NIH Office of Research Infrastructure Programs [P40 OD010440]
- National BioResource Project (NBRP)
- Canadian Institutes of Health Research (CIHR) [PJT-153199]
- Natural Sciences and Engineering Research Council of Canada (NSERC) [RGPIN-2018-05133]
- Cancer Research Society (CRS)
- National Institutes of Health (NIH) [R01AG051659, R56AG066682, R01AG044378]
- NSERC CGS-M
- NSERC CGS-D
- BCCHR scholarships
- ST by a Canada Research Chair
- BCCHR IGAP award
NHR-49, a nuclear hormone receptor in Caenorhabditis elegans, regulates a hypoxia response pathway that acts in parallel with HIF-1. In hypoxia, NHR-49 regulates a set of genes independent of HIF-1, including autophagy genes that promote hypoxia survival. NHR-67 acts as a negative regulator and HPK-1 acts as a positive regulator of the NHR-49 pathway.
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 (PPAR alpha). 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.
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