A1 Refereed original research article in a scientific journal
Regulation of starvation- and virus-induced autophagy by the eIF2 alpha kinase signaling pathway
Authors: Talloczy Z, Jiang WX, Virgin HW, Leib DA, Scheuner D, Kaufman RJ, Eskelinen EL, Levine B
Publisher: NATL ACAD SCIENCES
Publication year: 2002
Journal:Proceedings of the National Academy of Sciences of the United States of America
Journal name in sourcePROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Journal acronym: P NATL ACAD SCI USA
Volume: 99
Issue: 1
First page : 190
Last page: 195
Number of pages: 6
ISSN: 0027-8424
DOI: https://doi.org/10.1073/pnas.012485299
Abstract
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.
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.
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