title: Defects in the C. elegans acyl-CoA synthase, acs-3, and nuclear hormone receptor, nhr-25, cause sensitivity to distinct, but overlapping stresses.
abstract: Metazoan transcription factors control distinct networks of genes in specific tissues, yet understanding how these networks are integrated into physiology, development, and homeostasis remains challenging. Inactivation of the nuclear hormone receptor nhr-25 ameliorates developmental and metabolic phenotypes associated with loss of function of an acyl-CoA synthetase gene, acs-3. ACS-3 activity prevents aberrantly high NHR-25 activity. Here, we investigated this relationship further by examining gene expression patterns following acs-3 and nhr-25 inactivation. Unexpectedly, we found that the acs-3 mutation or nhr-25 RNAi resulted in similar transcriptomes with enrichment in innate immunity and stress response gene expression. Mutants of either gene exhibited distinct sensitivities to pathogens and environmental stresses. Only nhr-25 was required for wild-type levels of resistance to the bacterial pathogen P. aeruginosa and only acs-3 was required for wild-type levels of resistance to osmotic stress and the oxidative stress generator, juglone. Inactivation of either acs-3 or nhr-25 compromised lifespan and resistance to the fungal pathogen D. coniospora. Double mutants exhibited more severe defects in the lifespan and P. aeruginosa assays, but were similar to the single mutants in other assays. Finally, acs-3 mutants displayed defects in their epidermal surface barrier, potentially accounting for the observed sensitivities. Together, these data indicate that inactivation of either acs-3 or nhr-25 causes stress sensitivity and increased expression of innate immunity/stress genes, most likely by different mechanisms. Elevated expression of these immune/stress genes appears to abrogate the transcriptional signatures relevant to metabolism and development.
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Jordan D
authors.initials: JD
authors.lastname: Ward
authors.affiliation: Department of Physiology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Brendan
authors.initials: B
authors.lastname: Mullaney
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Schiller
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), UM2 Aix-Marseille Université, Marseille, France; Institut National de la Santé et de la Recherche Médicale (INSERM), Marseille, France; Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France.
authors.forename: Le D
authors.initials: LD
authors.lastname: He
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Petnic
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), UM2 Aix-Marseille Université, Marseille, France; Institut National de la Santé et de la Recherche Médicale (INSERM), Marseille, France; Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Couillault
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), UM2 Aix-Marseille Université, Marseille, France; Institut National de la Santé et de la Recherche Médicale (INSERM), Marseille, France; Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Pujol
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Teresita U
authors.initials: TU
authors.lastname: Bernal
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Marc R
authors.initials: MR
authors.lastname: Van Gilst
authors.affiliation: Department of Physiology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Kaveh
authors.initials: K
authors.lastname: Ashrafi
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), UM2 Aix-Marseille Université, Marseille, France; Institut National de la Santé et de la Recherche Médicale (INSERM), Marseille, France; Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Ewbank
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D023181:Antimicrobial Cationic Peptides / Q000235:genetics; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D003066:Coenzyme A Ligases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D056726:Genetic Association Studies; D008136:Longevity / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D034622:RNA Interference; D013312:Stress, Physiological; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
chemical_list: D023181:Antimicrobial Cationic Peptides; D004268:DNA-Binding Proteins; D014157:Transcription Factors; C486359:nuclear hormone receptor NHR-25, C elegans; D003066:Coenzyme A Ligases; D000098859:Long-Chain-Fatty-Acid-CoA Ligase