Ischemia-induced calpain activation causes eukaryotic (translation) initiation factor 4G1 (eIF4GI) degradation, protein synthesis inhibition, and neuronal death

Peter S. Vosler, Yanqin Gao, Christopher S. Brennan, Akiko Yanagiya, Yu Gan, Guodong Cao, Feng Zhang, Simon J. Morley, Nahum Sonenberg, Michael V. L. Bennett, Jun Chen

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Persistent protein synthesis inhibition (PSI) is a robust predictor of eventual neuronal death following cerebral ischemia. We thus tested the hypothesis that persistent PSI inhibition and neuronal death are causally linked. Neuronal viability strongly correlated with both protein synthesis and levels of eukaryotic (translation) initiation factor 4G1 (eIF4G1). We determined that in vitro ischemia activated calpain, which degraded eIF4G1. Overexpression of the calpain inhibitor calpastatin or eIF4G1 resulted in increased protein synthesis and increased neuronal viability compared with controls. The neuroprotective effect of eIF4G1 overexpression was due to restoration of cap-dependent protein synthesis, as well as protein synthesis-independent mechanisms, as inhibition of protein synthesis with cycloheximide did not completely prevent the protective effect of eIF4G1 overexpression. In contrast, shRNA-mediated silencing of eIF4G1 exacerbated ischemia-induced neuronal injury, suggesting eIF4G1 is necessary for maintenance of neuronal viability. Finally, calpain inhibition following global ischemia in vivo blocked decreases in eIF4G1, facilitated protein synthesis, and increased neuronal viability in ischemia-vulnerable hippocampal CA1 neurons. Collectively, these data demonstrate that calpain-mediated degradation of a translation initiation factor, eIF4G1, is a cause of both persistent PSI and neuronal death.

Original languageEnglish (US)
Pages (from-to)18102-18107
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number44
DOIs
StatePublished - Nov 1 2011

Fingerprint

Eukaryotic Initiation Factors
Calpain
Proteolysis
Ischemia
Proteins
Peptide Initiation Factors
Neuroprotective Agents
Cycloheximide
Brain Ischemia
Small Interfering RNA
Maintenance
Neurons

Keywords

  • Eukaryotic (translation) initiation factor 4g1 cleavage
  • Global ischemia

ASJC Scopus subject areas

  • General

Cite this

Ischemia-induced calpain activation causes eukaryotic (translation) initiation factor 4G1 (eIF4GI) degradation, protein synthesis inhibition, and neuronal death. / Vosler, Peter S.; Gao, Yanqin; Brennan, Christopher S.; Yanagiya, Akiko; Gan, Yu; Cao, Guodong; Zhang, Feng; Morley, Simon J.; Sonenberg, Nahum; Bennett, Michael V. L.; Chen, Jun.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 44, 01.11.2011, p. 18102-18107.

Research output: Contribution to journalArticle

Vosler, Peter S. ; Gao, Yanqin ; Brennan, Christopher S. ; Yanagiya, Akiko ; Gan, Yu ; Cao, Guodong ; Zhang, Feng ; Morley, Simon J. ; Sonenberg, Nahum ; Bennett, Michael V. L. ; Chen, Jun. / Ischemia-induced calpain activation causes eukaryotic (translation) initiation factor 4G1 (eIF4GI) degradation, protein synthesis inhibition, and neuronal death. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 44. pp. 18102-18107.
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