RRC ID 55880
著者 Goh GYS, Winter JJ, Bhanshali F, Doering KRS, Lai R, Lee K, Veal EA, Taubert S.
タイトル NHR-49/HNF4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting.
ジャーナル Aging Cell
Abstract Endogenous and exogenous stresses elicit transcriptional responses that limit damage and promote cell/organismal survival. Like its mammalian counterparts, hepatocyte nuclear factor 4 (HNF4) and peroxisome proliferator-activated receptor α (PPARα), Caenorhabditis elegans NHR-49 is a well-established regulator of lipid metabolism. Here, we reveal that NHR-49 is essential to activate a transcriptional response common to organic peroxide and fasting, which includes the pro-longevity gene fmo-2/flavin-containing monooxygenase. These NHR-49-dependent, stress-responsive genes are also upregulated in long-lived glp-1/notch receptor mutants, with two of them making critical contributions to the oxidative stress resistance of wild-type and long-lived glp-1 mutants worms. Similar to its role in lipid metabolism, NHR-49 requires the mediator subunit mdt-15 to promote stress-induced gene expression. However, NHR-49 acts independently from the transcription factor hlh-30/TFEB that also promotes fmo-2 expression. We show that activation of the p38 MAPK, PMK-1, which is important for adaptation to a variety of stresses, is also important for peroxide-induced expression of a subset of NHR-49-dependent genes that includes fmo-2. However, organic peroxide increases NHR-49 protein levels, by a posttranscriptional mechanism that does not require PMK-1 activation. Together, these findings establish a new role for the HNF4/PPARα-related NHR-49 as a stress-activated regulator of cytoprotective gene expression.
巻・号 17(3)
ページ e12743
公開日 2018-6-1
DOI 10.1111/acel.12743
PMID 29508513
PMC PMC5946062
MeSH Animals Caenorhabditis elegans / genetics* Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Fasting / metabolism* Fatty Acids / metabolism* Hepatocyte Nuclear Factor 4 / genetics* Lipid Metabolism / immunology* Oxidative Stress Receptors, Cytoplasmic and Nuclear / genetics* Signal Transduction
IF 7.346
引用数 15
リソース情報
線虫 tm1011 tm1978