Phosphorylation of eukaryotic initiation factor-2α (eIF2α) in autophagy

The integrated stress response is characterized by the phosphorylation of eukaryotic initiation factor-2 alpha (eIF2 alpha) on serine 51 by one out of four specific kinases (EIF2AK1 to 4). Here we provide three series of evidence suggesting that macroautophagy (to which we refer to as autophagy) induced by a variety of distinct pharmacological agents generally requires this phosphorylation event. First, the induction of autophagic puncta by various distinct compounds was accompanied by eIF2 alpha phosphorylation on serine 51. Second, the modulation of autophagy by >30 chemically unrelated agents was partially inhibited in cells expressing a non-phosphorylable (S51A) mutant of eIF2 alpha or lacking all four eIF2 alpha kinases, although distinct kinases were involved in the response to different autophagy inducers. Third, inhibition of eIF2 alpha phosphatases was sufficient to stimulate autophagy. In synthesis, it appears that eIF2 alpha phosphorylation is a central event for the stimulation of autophagy.