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  • The EMBO Journal (2004) 23, 169 - 179
  • doi:10.1038/sj.emboj.7600030

Published online: 8 January 2004

Cytoprotection by pre-emptive conditional phosphorylation of translation initiation factor 2

Phoebe D Lu1, Céline Jousse1, Stefan J Marciniak1, Yuhong Zhang1, Isabel Novoa1, Donalyn Scheuner2, Randal J Kaufman2, David Ron1 and Heather P Harding3

  1. Skirball Institute, New York University School of Medicine, New York, NY, USA
  2. Howard Hughes Medical Institute and the Department of Biochemistry, University of Michigan School of Medicine, Ann Arbor, MI, USA
  3. Department of Pharmacology, New York University School of Medicine, New York, NY, USA

Correspondence to:

David Ron, Skirball Institute, New York University School of Medicine, Third Floor, Lab 10, 540 First Avenue, New York, NY 10016, USA. Tel.: +1 212 263 7786; Fax: +1 212 263 8951; E-mail: ron@saturn.med.nyu.edu

Heather P Harding, E-mail: harding@saturn.med.nyu.edu

Received 23 June 2003; Accepted 27 October 2003

Transient phosphorylation of the alpha-subunit of translation initiation factor 2 (eIF2alpha) represses translation and activates select gene expression under diverse stressful conditions. Defects in the eIF2alpha phosphorylation-dependent integrated stress response impair resistance to accumulation of malfolded proteins in the endoplasmic reticulum (ER stress), to oxidative stress and to nutrient deprivations. To study the hypothesized protective role of eIF2alpha phosphorylation in isolation of parallel stress signaling pathways, we fused the kinase domain of pancreatic endoplasmic reticulum kinase (PERK), an ER stress-inducible eIF2alpha kinase that is normally activated by dimerization, to a protein module that binds a small dimerizer molecule. The activity of this artificial eIF2alpha kinase, Fv2E-PERK, is subordinate to the dimerizer and is uncoupled from upstream stress signaling. Fv2E-PERK activation enhanced the expression of numerous stress-induced genes and protected cells from the lethal effects of oxidants, peroxynitrite donors and ER stress. Our findings indicate that eIF2alpha phosphorylation can initiate signaling in a cytoprotective gene expression pathway independently of other parallel stress-induced signals and that activation of this pathway can single-handedly promote a stress-resistant preconditioned state.

  • Keywords:

    • preconditioning,
    • protein kinases,
    • reactive oxygen species,
    • signal transduction,
    • translation