The protein kinase Gcn2p mediates sodium toxicity in yeast

Phosphorylation of the a-subunit of eukaryotic initiation factor 2 (eIF2 al pha) is a conserved mechanism regulating protein synthesis in response to v arious stresses. A screening for negative factors in yeast salt stress tole rance has led to the identification of Gcn2p, the single yeast eIF2a kinase that is activated by amino acid starvation in the general amino acid contr ol response. Mutation of other components of this regulatory circuit such a s GCN1 and GCN3 also resulted in improved NaCl tolerance. The gcn2 phenotyp e was not accompanied by changes in sodium or potassium homeostasis. NaCl i nduced a Gcn2p-dependent phosphorylation of eIF2a and translational activat ion of Gcn4p, the transcription factor that mediates the general amino acid control response. Mutations that activate Gcn4p function, such as gcd7-201 , cpc2, and deletion of the translational regulatory region of the GCN4 gen e, also cause salt sensitivity. It can be postulated that sodium activation of the Gcn2p pathway has toxic effects on growth under NaCl stress and tha t this novel mechanism of sodium toxicity may be of general significance in eukaryotes.