title: Growing rats respond to a sulfur amino acid-deficient diet by phosphorylation of the alpha subunit of eukaryotic initiation factor 2 heterotrimeric complex and induction of adaptive components of the integrated stress response.
abstract: Mammalian cells respond to various kinds of stress, including nutritional stress, via pathways that are initiated by phosphorylation of the alpha subunit of the eukaryotic initiation factor 2 complex (eIF2alpha). Because the models used to study eIF2alpha-kinase-mediated responses to amino acid deficiency have commonly used media or diets devoid of 1 or more essential amino acids, we asked whether eIF2alpha-kinase-mediated responses would be induced in animals fed a more typical diet that was not as imbalanced as one in which 1 essential amino acid is totally absent. To answer this question, we fed rats soy protein-based diets that were either adequate or limiting in sulfur-containing amino acids (SAA). Rats fed a SAA-deficient diet (3.4 g methionine equivalents/kg diet) grew more slowly than rats fed the control diet (5.86 g methionine equivalents/kg diet). Analysis of liver from rats fed these diets for 7 d showed that the SAA-deficient rats had higher levels of eIF2alpha phosphorylation and higher levels of activating transcription factor (ATF) 4, ATF3, asparagine synthetase, solute carrier 7A11, cysteinyl-tRNA synthetase, and cystathionine gamma-lyase. On the other hand, components of the integrated stress response (ISR) known to promote apoptosis or translational recovery were not induced. Taken together, our results indicate that rats fed the SAA-deficient diet had a prolonged activation of an eIF2alpha kinase that leads to upregulation of adaptive components of the ISR.
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Angelos K
authors.initials: AK
authors.lastname: Sikalidis
authors.forename: Martha H
authors.initials: MH
authors.lastname: Stipanuk
mesh_terms: D000222:Adaptation, Physiological; D000603:Amino Acids, Sulfur / Q000494:pharmacology*; D000818:Animals; D004032:Diet; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005247:Feeding Behavior / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D008099:Liver / Q000378:metabolism; D008297:Male; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013312:Stress, Physiological / Q000502:physiology*; D015430:Weight Gain / Q000187:drug effects*
chemical_list: D000603:Amino Acids, Sulfur; D015852:Eukaryotic Initiation Factor-2