Regulation of starvation- and virus-induced autophagy by the eIF2 alpha kinase signaling pathway

: Talloczy Z, Jiang WX, Virgin HW, Leib DA, Scheuner D, Kaufman RJ, Eskelinen EL, Levine B

Publisher: NATL ACAD SCIENCES

: 2002

: Proceedings of the National Academy of Sciences of the United States of America

: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

: P NATL ACAD SCI USA

: 99

: 1

: 190

: 195

: 6

: 0027-8424

DOI: https://doi.org/10.1073/pnas.012485299

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.