title: Mitochondrial SKN-1/Nrf mediates a conserved starvation response.
abstract: SKN-1/Nrf plays multiple essential roles in development and cellular homeostasis. We demonstrate that SKN-1 executes a specific and appropriate transcriptional response to changes in available nutrients, leading to metabolic adaptation. We isolated gain-of-function (gf) alleles of skn-1, affecting a domain of SKN-1 that binds the transcription factor MXL-3 and the mitochondrial outer membrane protein PGAM-5. These skn-1(gf) mutants perceive a state of starvation even in the presence of plentiful food. The aberrant monitoring of cellular nutritional status leads to an altered survival response in which skn-1(gf) mutants transcriptionally activate genes associated with metabolism, adaptation to starvation, aging, and survival. The triggered starvation response is conserved in mice with constitutively activated Nrf and may contribute to the tumorgenicity associated with activating Nrf mutations in mammalian somatic cells. Our findings delineate an evolutionarily conserved metabolic axis of SKN-1/Nrf, further establishing the complexity of this pathway.
authors.affiliation: Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Paek
authors.forename: Jacqueline Y
authors.initials: JY
authors.lastname: Lo
authors.forename: Sri Devi
authors.initials: SD
authors.lastname: Narasimhan
authors.forename: Tammy N
authors.initials: TN
authors.lastname: Nguyen
authors.forename: Kira
authors.initials: K
authors.lastname: Glover-Cutter
authors.forename: Stacey
authors.initials: S
authors.lastname: Robida-Stubbs
authors.forename: Takafumi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: T Keith
authors.initials: TK
authors.lastname: Blackwell
authors.forename: Sean P
authors.initials: SP
authors.lastname: Curran
mesh_terms: D000483:Alleles; D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation; D051265:NF-E2-Related Factor 1 / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D013217:Starvation; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D051265:NF-E2-Related Factor 1; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C541018:WDR-23 protein, C elegans; C073702:skn-1 protein, C elegans; D038362:Glycogen Synthase Kinase 3; D010744:Phosphoric Monoester Hydrolases