Methylglyoxal activates Gcn2 to phosphorylate eIF2α independently of the TOR pathway in Saccharomyces cerevisiae.

Abstract

Methylglyoxal is a ubiquitous 2-oxoaldehyde derived from glycolysis. Previously, we have reported that methylglyoxal attenuates the rate of overall protein synthesis in Saccharomyces cerevisiae through phosphorylation of the alpha subunit of translation initiation factor 2 (eIF2alpha) in a Gcn2-dependent manner. Phosphorylation of eIF2alpha impedes the formation of a translation initiation complex, and subsequently, overall protein synthesis is reduced. Uncharged tRNA plays an important role in the activation of Gcn2, although we found that MG treatment did not elevate the levels of uncharged tRNA. Rapamycin, a potent inhibitor of TOR kinase, is known to induce phosphorylation of eIF2alpha without affecting the levels of uncharged tRNA. We determined the correlation between methylglyoxal and TOR kinase activity and found that phosphorylation of eIF2alpha by methylglyoxal occurred independently of the target of rapamycin (TOR) pathway.