Regulation of starvation- and virus-induced autophagy by the eIF2alpha kinase signaling pathway.
The eIF2alpha kinases are a family of evolutionarily conserved serine/threonine kinases that regulate stress-induced translational arrest. Here, we demonstrate that the yeast eIF2alpha kinase, GCN2, the target phosphorylation site of Gcn2p, Ser-51 of eIF2alpha, and the eIF2alpha-regulated transcriptional transactivator, GCN4, are essential for another fundamental stress response, starvation-induced autophagy. The mammalian IFN-inducible eIF2alpha kinase, PKR, rescues starvation-induced autophagy in GCN2-disrupted yeast, and pkr null and Ser-51 nonphosphorylatable mutant eIF2alpha murine embryonic fibroblasts are defective in autophagy triggered by herpes simplex virus infection. Furthermore, PKR and eIF2alpha Ser-51-dependent autophagy is antagonized by the herpes simplex virus neurovirulence protein, ICP34.5. Thus, autophagy is a novel evolutionarily conserved function of the eIF2alpha kinase pathway that is targeted by viral virulence gene products.
Tallóczy
Zsolt
Z
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Jiang
Wenxia
W
Virgin
Herbert W
HW
Leib
David A
DA
Scheuner
Donalyn
D
Kaufman
Randal J
RJ
Eskelinen
Eeva-Liisa
EL
Levine
Beth
B
D000818:Animals; D001665:Binding Sites; D015153:Blotting, Western; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D005347:Fibroblasts / Q000378:metabolism; D005656:Fungal Proteins / Q000502:physiology*; D007150:Immunohistochemistry; D051379:Mice; D009154:Mutation; D010587:Phagocytosis; D010766:Phosphorylation; D011485:Protein Binding; D011494:Protein Kinases / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D018139:Simplexvirus / Q000378:metabolism / Q000472:pathogenicity; D013997:Time Factors; D015533:Transcriptional Activation; D014764:Viral Proteins / Q000378:metabolism; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D029701:Saccharomyces cerevisiae Proteins; D014764:Viral Proteins; C066469:gamma 34.5 protein, Human herpesvirus 1; D012694:Serine; D011494:Protein Kinases; D019892:eIF-2 Kinase