Regulation of starvation- and virus-induced autophagy by the eIF2α kinase signaling pathway

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 99; no. 1; pp. 190 - 195
• Main Authors: Talloczy, Z, Jiang, W, Virgin IV, HW, Leib, DA, Scheuner, D, Kaufman, R J, Eskelinen, E, Levine, B
• Format: Journal Article
• Language: English
• Published: National Acad Sciences 08.01.2002; The National Academy of Sciences
• Subjects: Biological Sciences; eIF2a kinase; GCN2 gene; GCN4 gene; Herpes simplex virus; ICP34.5 protein
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.012485299

The eIF2α kinases are a family of evolutionarily conserved serine/threonine kinases that regulate stress-induced translational arrest. Here, we demonstrate that the yeast eIF2α kinase, GCN2 , the target phosphorylation site of Gcn2p, Ser-51 of eIF2α, and the eIF2α-regulated transcriptional transactivator, GCN4 , are essential for another fundamental stress response, starvation-induced autophagy. The mammalian IFN-inducible eIF2α kinase, PKR, rescues starvation-induced autophagy in GCN2 -disrupted yeast, and pkr null and Ser-51 nonphosphorylatable mutant eIF2α murine embryonic fibroblasts are defective in autophagy triggered by herpes simplex virus infection. Furthermore, PKR and eIF2α 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 eIF2α kinase pathway that is targeted by viral virulence gene products.