5 Nutrient signaling through mammalian GCN2

Abstract

mGCN2 is the mammalian ortholog of the protein kinase Gcn2p that is activated in Saccharomyces cerevisiae in response to nutrient starvation. In mammalian cells in culture, mGCN2 is also activated by deprivation of essential amino acids. However, in animals in vivo, mGCN2 is not activated by physiological changes in plasma amino acid concentrations such as occur in response to feeding. Instead, mGCN2 is activated in response to feeding a diet lacking single essential amino acids, suggesting that imbalanced plasma essential amino acid levels are involved in the response. The only known substrate for mGCN2 is the α-subunit of the translation initiation factor, eIF2. Hyperphosphorylation of eIF2α represses the translation of most mRNAs. However, in both yeast and mammals, amino acid deprivation results in only partial phosphorylation of eIF2α, such that the translation of most mRNAs is incompletely repressed. Moreover, the translation of a few mRNAs is enhanced by eIF2α phosphorylation, in particular translation of the mRNAs encoding the transcription factors Gcn4p and ATF4 is stimulated in yeast and mammals, respectively, in response to amino acid deprivation. In each case, the genes induced by the transcription factors provide a mechanism for relieving the stress induced by nutrient starvation.