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Cytoprotection by pre‐emptive conditional phosphorylation of translation initiation factor 2
Author(s) -
Lu Phoebe D,
Jousse Céline,
Marciniak Stefan J,
Zhang Yuhong,
Novoa Isabel,
Scheuner Donalyn,
Kaufman Randal J,
Ron David,
Harding Heather P
Publication year - 2004
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600030
Subject(s) - eif2 , endoplasmic reticulum , biology , phosphorylation , unfolded protein response , microbiology and biotechnology , eif 2 kinase , signal transduction , translation (biology) , protein kinase a , biochemistry , gene , cyclin dependent kinase 2 , messenger rna
Transient phosphorylation of the α‐subunit of translation initiation factor 2 (eIF2α) represses translation and activates select gene expression under diverse stressful conditions. Defects in the eIF2α 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 eIF2α phosphorylation in isolation of parallel stress signaling pathways, we fused the kinase domain of pancreatic endoplasmic reticulum kinase (PERK), an ER stress‐inducible eIF2α kinase that is normally activated by dimerization, to a protein module that binds a small dimerizer molecule. The activity of this artificial eIF2α 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 eIF2α 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.