A selective inhibitor of elF2 dephosphorylation protects cells from ER stress (Science, 307:935-939, 11 February 2005)

報告日期: 2005/10/21
報告時間: 16:00/16:50
報告學生: 黃浩綸
講評老師: 沈孟儒
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A Selective Inhibitor of eIF2a Dephosphorylation Protects Cells from ER Stress

SCIENCE, 307: 935-939,2005

 

Speaker 黃浩綸                                Date: 2005/10/21

Commentator 沈孟儒老師                          Place: Room 601

 

Abstract

   The endoplasmic reticulum (ER) is a principal site for protein synthesis and folding, calcium storage and calcium signaling. Depletion of calcium levels from the ER lumen, inhibitors of glycosylation, chemical toxicants, oxidative stress and/or accumulation of misfolded or unfolded proteins in the ER can all disrupt ER function, resulting in what has been referred to as ‘ER stress’. However, excessive and uncorrected ER stress can induce cell apoptosis, which has been implicated in many important pathologies, viral infection. All eukaryotes respond to ER stress through a set of pathways known as the unfolded protein response (UPR). The PERK (the PKR-like ER kinase) of the UPR has been implicated in inhibition of initiation of protein synthesis by phosphorylating thesubunit of eukaryotic translation initiation factor 2 (eIF2a) at serine 51 in cells subjected to various forms of stress including virus infection. Most protein phosphatases have little intrinsic substrate specificity, making selective pharmacological inhibition of specific dephosphorylation reactions a challenging problem. In a screen for compounds that protect mammalian cells from apoptosis induced by ER stress, the authors identified a small molecule, termed salubrinal. Salubrinal protects cells against ER stress by blocking eIF2adephosphorylation via inhibiting the protein complex GADD34/PP1 consisting of the general cellular serine/threonine phosphatase PP1 and the non-enzymatic cofactor GADD34. It inhibits eIF2a dephosphorylation mediated by a herpes simplex virus encoded protein and blocks viral replication in vitro and in vivo. This suggest that the inhibition of eIF2a dephosphorylation may be a potent therapeutic strategy in diseases involving ER stress and viral infection, and that such small molecule as salubrinal might find therapeutic use in these diseases.

 

References

1. R. V. Rao, et al., Cell Death Differ. 11, 372 (2004).

2. Kai Long, et al., Bioorg Med Chem Lett. 15, 3849 (2005)