Phosphorylation of eIF2α at serine 51 is an important determinant of cell survival and adaptation to glucose deficiency.
Various forms of stress induce pathways that converge on the phosphorylation of the alpha (α) subunit of eukaryotic translation initiation factor eIF2 at serine 51 (S51), a modification that results in a global inhibition of protein synthesis. In many cases eIF2α phosphorylation is a biological response that facilitates cells to cope with stressful environments. Glucose deficiency, an important form of stress, is associated with an induction of apoptosis. Herein, we demonstrate that eIF2α phosphorylation is a key step in maintaining a balance between the life and death of a glucose-deficient cell. That is, eIF2α phosphorylation acts as a molecular switch that shifts cells from a proapoptotic to a cytoprotective state in response to prolonged glucose deficiency. This adaptation process is associated with the timely expression of proteins and activation of pathways with significant contributions to cell survival and adaptation including the X-linked inhibitor of apoptosis protein (XIAP). We also show that among the eIF2α kinases GCN2 plays a proapoptotic role whereas PERK and PKR play a cytoprotective one in response to glucose deficiency. Our data demonstrate that eIF2α phosphorylation is a significant determinant of survival and adaptation of glucose-deficient cells with possible important implications in biological processes that interfere with glucose metabolism.
Muaddi
Hala
H
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, QC, H3T 1E2, Canada.
Majumder
Mithu
M
Peidis
Philippos
P
Papadakis
Andreas I
AI
Holcik
Martin
M
Scheuner
Donalyn
D
Kaufman
Randal J
RJ
Hatzoglou
Maria
M
Koromilas
Antonis E
AE
D000220:Adaptation, Biological; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology*; D002478:Cells, Cultured; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D005947:Glucose / Q000172:deficiency*; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
D015852:Eukaryotic Initiation Factor-2; D005947:Glucose; D034741:RNA, Small Interfering; D012694:Serine; D051636:X-Linked Inhibitor of Apoptosis Protein; D019892:eIF-2 Kinase