Presentation/Session Information

Session Information

Session Title: Physiology: Aging and Stress II Session Type: Parallel
Session Location: Carnesale Palisades Ballroom Session Time: Fri, Jun 26 8:30AM - 11:30AM

Presentation Information

Program Number: 83 Presentation Time: 10:54AM - 11:06AM

Presentation Content

A novel role for the nuclear receptor NHR-49 in the oxidative stress response.Grace Y.S. Goh, Regina C. Lai, Ka-Young Lee, Stefan Taubert. University of British Columbia, Vancouver,

Cytoprotective responses and lipid metabolism are tied to longevity. Genes in both pathways are differentially regulated in several long-lived mutants, and many regulators of these genes are key effectors of longevity. One such regulator is the transcriptional coregulator MDT-15, a subunit of the Mediator complex. MDT-15 regulates lipid metabolism and oxidative stress response genes, and is required for normal lifespan. In the oxidative stress response, MDT-15 binds the transcription factor SKN-1 and regulates SKN-1-dependent genes. However, not all oxidative stress response genes are SKN-1-dependent. For example, the tert-butyl hydroperoxide (tBOOH) response is largely SKN-1-independent. We previously showed that MDT-15 is required for the tBOOH response; however, the transcription factor that regulates this response is unknown.

The MDT-15 KIX domain interacts with multiple transcription factors. We found that a gain-of-function (GOF) mutation of mdt-15 located near the KIX specifically induces SKN-1-independent tBOOH-responsive genes. This implies that the tBOOH response is regulated by a transcription factor that binds the KIX domain of MDT-15. We conducted an RNAi screen to find transcription factors required to induce a promoter::GFP fusion of fmo-2, a tBOOH-responsive gene. We tested transcription factors that bind the KIX domain of MDT-15, as determined by published screens. Of the candidates screened, only the nuclear receptor NHR-49 was required for fmo-2p::GFP induction on tBOOH. NHR-49 is required to express genes involved in lipid metabolism, including β-oxidation and fatty acid desaturation, but has not been implicated in oxidative stress responses. Using qPCR, we show that nhr-49 null mutants fail to fully induce other tBOOH-responsive genes in addition to fmo-2. Conversely, nhr-49 GOF mutants show upregulation of many tBOOH-responsive genes even without tBOOH. Interestingly, we previously found that nhr-49 nulls are hypersensitive to tBOOH; therefore, the regulation of tBOOH-responsive genes by NHR-49 also has functional consequences. We are currently testing whether any known NHR-49 partners, e.g. NHR-80 or NHR-13, are also required for the tBOOH response.

In conclusion, we describe a new role for NHR-49 as a regulator of the oxidative stress response. NHR-49 has recently emerged as an important regulator of longevity, e.g. in germline-less glp-1 mutants. This was thought to relate to nhr-49’s role in lipid metabolism. Our work suggests an alternative possibility, i.e. that NHR-49’s role in the oxidative stress response contributes to its action in longevity pathways.

Please note: Abstract shown here should NOT be cited in bibliographies. Material contained herein should be treated as personal communication and should be cited as such only with the consent of the author.

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