eIF2α phosphorylation tips the balance to apoptosis during osmotic stress

Elena Bevilacqua, Xinglong Wang, Mithu Majumder, Francesca Gaccioli, Celvie L. Yuan, Chuanping Wang, Xiongwei Zhu, Lindsay E. Jordan, Donalyn Scheuner, Randal J. Kaufman, Antonis E. Koromilas, Martin D. Snider, Martin Holcik, Maria Hatzoglou

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

Abstract

Regulation of cell volume is of great importance because persistent swelling or shrinkage leads to cell death. Tissues experience hypertonicity in both physiological (kidney medullar cells) and pathological states (hypernatremia). Hypertonicity induces an adaptive gene expression program that leads to cell volume recovery or apoptosis under persistent stress. We show that the commitment to apoptosis is controlled by phosphorylation of the translation initiation factor eIF2α, the master regulator of the stress response. Studies with cultured mouse fibroblasts and cortical neurons show that mutants deficient in eIF2α phosphorylation are protected from hypertonicity- induced apoptosis. A novel link is revealed between eIF2α phosphorylation and the subcellular distribution of the RNA-binding protein heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1). Stress-induced phosphorylation of eIF2α promotes apoptosis by inducing the cytoplasmic accumulation of hnRNP A1, which attenuates internal ribosome entry site-mediated translation of anti-apoptotic mRNAs, including BclxL that was studied here. Hypertonic stress induced the eIF2α phosphorylation-independent formation of cytoplasmic stress granules (SGs, structures that harbor translationally arrested mRNAs) and the eIF2α phosphorylation-dependent accumulation of hnRNP A1 in SGs. The importance of hnRNP A1 was demonstrated by induction of apoptosis in eIF2α phosphorylation-deficient cells that express exogenous cytoplasmic hnRNP A1. We propose that eIF2α phosphorylation during hypertonic stress promotes apoptosis by sequestration of specific mRNAs in SGs in a process mediated by the cytoplasmic accumulation of hnRNP A1.

Original languageEnglish (US)
Pages (from-to)17098-17111
Number of pages14
JournalJournal of Biological Chemistry
Volume285
Issue number22
DOIs
StatePublished - May 28 2010
Externally publishedYes

Keywords

  • Cell death
  • IRES
  • Protein synthesis
  • Signal transduction
  • Stress granule
  • Translation
  • hnRNPs

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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