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Review
. 2015 Jul 17;16(7):16275-87.
doi: 10.3390/ijms160716275.

Experimental Evidence Shows Salubrinal, an eIF2α Dephosphorylation Inhibitor, Reduces Xenotoxicant-Induced Cellular Damage

Masato Matsuoka  1 , Yuta Komoike  2
Affiliations
Review

Experimental Evidence Shows Salubrinal, an eIF2α Dephosphorylation Inhibitor, Reduces Xenotoxicant-Induced Cellular Damage

Masato Matsuoka et al. Int J Mol Sci. .

Abstract

Accumulating evidence indicates that endoplasmic reticulum (ER) stress and the subsequent unfolded protein response (UPR) are involved in the pathogenesis of not only the protein misfolding disorders such as certain neurodegenerative and metabolic diseases, but also in the cytotoxicity of environmental pollutants, industrial chemicals, and drugs. Thus, the modulation of ER stress signaling pathways is an important issue for protection against cellular damage induced by xenotoxicants. The substance salubrinal has been shown to prevent dephosphorylation of the eukaryotic translation initiation factor 2 alpha (eIF2α). The phosphorylation of eIF2α appears to be cytoprotective during ER stress, because inhibition of the translation initiation activity of eIF2α reduces global protein synthesis. In addition, the expression of activating transcription factor 4 (ATF4), a transcription factor that induces the expression of UPR target genes, is up-regulated through alternative translation. This review shows that salubrinal can protect cells from the damage induced by a wide range of xenotoxicants, including environmental pollutants and drugs. The canonical and other possible mechanisms of cytoprotection by salubrinal from xenotoxicant-induced ER stress are also discussed.

Keywords: ATF4; ER stress; apoptosis; cytoprotection; drugs; eIF2α; environmental pollutants; salubrinal; xenotoxicants.

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Figures

Figure 1
Figure 1
Inhibition of eIF2α dephosphorylation by salubrinal. During ER stress, the double-stranded RNA-activated protein kinase-like ER kinase (PERK) phosphorylates the eukaryotic translation initiation factor 2 alpha (eIF2α). Salubrinal prevents eIF2α dephosphorylation by inhibiting the protein complex GADD34/PP1, which consists of the general cellular serine/threonine protein phosphatase 1 (PP1) and the non-enzymatic cofactor growth arrest and DNA damage gene 34 (GADD34).
Figure 2
Figure 2
Proposed effects of salubrinal on the xenotoxicant-activated ER stress signaling pathways. Following exposure to xenotoxicants, ER stress activates the double-stranded RNA-activated protein kinase-like ER kinase (PERK)/eukaryotic translation initiation factor 2 alpha (eIF2α) pathway and the inositol-requiring enzyme 1 (IRE1)/tumor necrosis factor receptor-associated factor 2 (TRAF2) pathway, which are the two branches of the unfolded protein response (UPR). The enhancement or prolongation of eIF2α phosphorylation by salubrinal reduces global protein synthesis and the overall amount of ER stress, resulting in cell survival. In contrast to most proteins, the expression of activating transcription factor 4 (ATF4) is up-regulated through alternative translation and thus not impacted by the reduction in protein synthesis. The ATF4 protein balances between the signals leading to survival (by 78-kDa glucose-regulated protein (GRP78) and other UPR targets) and to apoptosis (by CCAAT/enhancer-binding protein homologous protein (CHOP)). Salubrinal might act on the IRE1/TRAF2 pathway that leads to the activation of apoptosis signal-regulating kinase 1 (ASK1)/c-Jun NH2-terminal kinase (JNK)-mediated, ASK1/p38-mediated, and caspase-12-dependent apoptotic pathways.
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References

    1. Brostrom M.A., Brostrom C.O. Calcium dynamics and endoplasmic reticular function in the regulation of protein synthesis: Implications for cell growth and adaptability. Cell Calcium. 2003;34:345–363. doi: 10.1016/S0143-4160(03)00127-1. - DOI - PubMed
    1. Ron D., Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 2007;8:519–529. doi: 10.1038/nrm2199. - DOI - PubMed
    1. Schröder M., Kaufman R.J. ER stress and the unfolded protein response. Mutat. Res. 2005;569:29–63. doi: 10.1016/j.mrfmmm.2004.06.056. - DOI - PubMed
    1. Inagi R. Endoplasmic reticulum stress as a progression factor for kidney injury. Curr. Opin. Pharmacol. 2010;10:156–165. doi: 10.1016/j.coph.2009.11.006. - DOI - PubMed
    1. Mori K. Tripartite management of unfolded proteins in the endoplasmic reticulum. Cell. 2000;101:451–454. doi: 10.1016/S0092-8674(00)80855-7. - DOI - PubMed

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