Nuclear hormone receptor NHR-49 acts in parallel with HIF-1 to promote hypoxia adaptation in Caenorhabditis elegans

Curation statements for this article:
  • Curated by eLife

    eLife logo

    Evaluation Summary:

    This study brings new insight into how organisms maintain homeostasis under stress conditions and has implications for our understanding both development and disease. The study provides evidence that NHR-49 protects animals from hypoxia by activating autophagy, and that it acts independently of the well-described canonical HIF-1 hypoxia response. The experiments are well done, and the conclusions from the results are largely appropriate. The impact of this study will be highest in the specific field of hypoxia, with more moderate impact for wider audiences interested in understanding of how biological maintain homeostasis under stress.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

This article has been Reviewed by the following groups

Read the full article See related articles

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 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.

Article activity feed

  1. Author Response:

    Reviewer #1 (Public Review):

    Summary

    The authors have discovered and characterized a novel genetic pathway responsive to hypoxia, which acts in parallel to the canonical response through activation of Hypoxia-Inducible Factor (HIF). Specifically, the authors discovered that the Caenorhabditis elegans nuclear hormone receptor NHR-49, ortholog to mammalian PPAR-alpha, is essential for survival under hypoxic conditions and regulates target gene expression that is hif-1-independent; identifying an essential role of autophagy. Further the authors discover both positive and negative regulators of NHR-49 and a putative feedback loop.

    Overall analysis

    The genetic analysis conducted by the authors is outstanding. However, the study is lacking in a few key areas and the authors may have over-interpreted results in a few …

  2. Evaluation Summary:

    This study brings new insight into how organisms maintain homeostasis under stress conditions and has implications for our understanding both development and disease. The study provides evidence that NHR-49 protects animals from hypoxia by activating autophagy, and that it acts independently of the well-described canonical HIF-1 hypoxia response. The experiments are well done, and the conclusions from the results are largely appropriate. The impact of this study will be highest in the specific field of hypoxia, with more moderate impact for wider audiences interested in understanding of how biological maintain homeostasis under stress.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. …

  3. Reviewer #1 (Public Review):

    Summary:

    The authors have discovered and characterized a novel genetic pathway responsive to hypoxia, which acts in parallel to the canonical response through activation of Hypoxia-Inducible Factor (HIF). Specifically, the authors discovered that the Caenorhabditis elegans nuclear hormone receptor NHR-49, ortholog to mammalian PPAR-alpha, is essential for survival under hypoxic conditions and regulates target gene expression that is hif-1-independent; identifying an essential role of autophagy. Further the authors discover both positive and negative regulators of NHR-49 and a putative feedback loop.

    Overall analysis:

    The genetic analysis conducted by the authors is outstanding. However, the study is lacking in a few key areas and the authors may have over-interpreted results in a few places, which diminishes …

  4. Reviewer #2 (Public Review):

    The data provided in the manuscript is mostly of good quality and the interpretations are sound. However, since the central message of this paper is characterization of this HIF-1-independent hypoxia response pathway, some more mechanistic detail needs to be provided. How the kinase HPK-1 activates NHR-49 specifically in hypoxic conditions needs some further investigation using biochemical approaches. In addition, the reciprocal inhibitory relationship between nhr-49 and nhr-67 during hypoxia should be explored a bit further because both the NHRs seem to promote survival in hypoxic conditions, but it is not clear whether they do so via the same or parallel pathways.

  5. Reviewer #3 (Public Review):

    Here, the authors identify a HIF-independent pathway controlled by NHR-49 in the C. elegans system. Authors hypothesized that nhr-49 has a role in hypoxia and regulates fmo-2 and genes involved with autophagy. Genetic analysis indicates that nhr-49 is required for hypoxia survival. Transcriptomic studies show that NHR-49 regulates a set of genes in hypoxia, that are HIF-1 independent. Authors provide evidence that NHR-67 is a negative regulator and HPK-1 is a positive regulator of the NHR-49 pathway. Authors found that autophagy gene dysfunction compromized hypoxia survival. It is unclear if the NHR-67 and HPK-1 regulators of NHR-49 impact the genes involved with autophagy as most transcriptional readout assays were done with the fmo-2 and acs-2 reporters. However, authors convincingly show that NHR-49 is …