A critical role of eEF-2K in mediating autophagy in response to multiple cellular stresses.
The phosphorylation of the subunit alpha of eukaryotic translation initiation factor 2 (eIF2alpha), a critical regulatory event in controlling protein translation, has recently been found to mediate the induction of autophagy. However, the mediators of autophagy downstream of eIF2alpha remain unknown. Here, we provide evidence that eIF2alpha phosphorylation is required for phosphorylation of eukaryotic elongation factor 2 (eEF-2) during nutrient starvation. In addition, we show that eukaryotic elongation factor 2 kinase (eEF-2K) is also required for autophagy signaling during ER stress, suggesting that phosphorylation of eEF-2 may serve as an integrator of various cell stresses for autophagy signaling. On the other hand, although the activation of eEF-2K in response to starvation requires the phosphorylation of eIF2alpha, additional pathways relying partly on Ca(2+) flux may control eEF-2K activity during ER stress, as eIF2alpha phosphorylation is dispensable for both eEF-2 phosphorylation and autophagy in this context.
Py
Bénédicte F
BF
Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
Boyce
Michael
M
Yuan
Junying
J
D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D003470:Culture Media / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D054736:Elongation Factor 2 Kinase / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D051379:Mice; D020652:Peptide Elongation Factor 2 / Q000378:metabolism; D010766:Phosphorylation; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction
D003470:Culture Media; D015852:Eukaryotic Initiation Factor-2; D020652:Peptide Elongation Factor 2; D011500:Protein Synthesis Inhibitors; D034741:RNA, Small Interfering; D003513:Cycloheximide; D054736:Elongation Factor 2 Kinase; D002118:Calcium