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.