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PMID: 11756670 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Regulation of starvation- and virus-induced autophagy by the eIF2alpha kinase signaling pathway.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 99 ·No. 1 ·2002-01-08 ·Pages 190-5

Tallóczy Z, Jiang W, Virgin HW, Leib DA, Scheuner D, Kaufman RJ, Eskelinen EL, Levine B

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.

MeSH Terms
Animals Binding Sites Blotting, Western Cells, Cultured DNA-Binding Proteins Fibroblasts/metabolism Fungal Proteins/physiology Immunohistochemistry Mice Mutation Phagocytosis Phosphorylation Protein Binding Protein Kinases/physiology Saccharomyces cerevisiae Proteins Serine/chemistry Signal Transduction Simplexvirus/metabolism,pathogenicity Time Factors Transcriptional Activation Viral Proteins/metabolism eIF-2 Kinase/genetics,metabolism
Chemicals
DNA-Binding Proteins Fungal Proteins Saccharomyces cerevisiae Proteins Viral Proteins gamma 34.5 protein, Human herpesvirus 1 Serine Protein Kinases eIF-2 Kinase
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Tallóczy Zsolt
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Jiang Wenxia
Virgin Herbert W
Leib David A
Scheuner Donalyn
Kaufman Randal J
Eskelinen Eeva-Liisa
Levine Beth
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.012485299
Published
2002-01-08
Epub
2001-00-26
Pages
190-5
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC117537
Subset
IM
Grants
NCI NIH HHS · R01 CA084254 · United States
NEI NIH HHS · R01 EY09083 · United States
NEI NIH HHS · R01 EY009083 · United States
NIAID NIH HHS · R01 AI39616 · United States
NCI NIH HHS · R01 CA84254 · United States
NIAID NIH HHS · AI42394 · United States
NIAID NIH HHS · R01 AI44157 · United States
NIAMS NIH HHS · R01 AR45019 · United States
External Links
PubMed source DOI: 10.1073/pnas.012485299 PMC Full Text View journal details
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