Newly Discovered Compound Protects Cells from Endoplasmic Reticulum Stress

David Ron, MD
New York University School of Medicine
R01ES08681

Background: The endoplasmic reticulum (ER) is a membranous labyrinth so extensive that it accounts for more than half the total membrane in many cells. There are two forms of ER—rough and smooth. Rough ER is dotted with ribosomes which are the protein factories of the cell. Smooth ER has no ribosomes attached. The two forms together are the site of a wide variety of cellular functions including detoxification of drugs and other xenobiotics, carbohydrate metabolism, protein, fat, and steroid synthesis, folding of proteins, and transporting these molecules to other parts of the cell.

A condition known as ER stress is defined as the inability of the ER to fold proteins properly. It results from a diverse group of human diseases including viral infections, diabetes, neurodegeneration, etc. The accumulation of unfolded proteins in the endoplasmic reticulum (ER) is sensed by cells and initiates a stress response logically called the unfolded protein response (UPR). The UPR is a set of pathways that decreases protein synthesis. Failure of the UPR to correct ER stress results in apoptosis or programmed cell death.

Advance: Employing a high-throughput screening approach of approximately 19,000 chemicals, a team of NIH-supported researchers recently discovered a small molecule that enables cells to withstand ER stress. The compound, dubbed salubrinal, works to stop cell death by inducing the phosphorylation (activation) of a key component of the UPR known as eIF2α (eukaryotic translation initiation factor 2, subunit α). Further experiments demonstrated that salubrinal was both more specific and more selective than other phosphatase inhibitors. Next to examine the compound's effectiveness in disease processes, the investigators examined its effects on herpes simplex infection. They found that salubrinal inhibits both eIF2α dephosphorylation mediated by the virus and viral replication. Salubrinal also reduced the amount of virus found in eye swabs of a mouse herpes simplex virus cornea infection model.

Implications: These results provide a ”proof-of-principle” of the feasibility of producing research reagents and drugs to block dephosphorylation of selective cellular products. The authors conclude that ”selective small-molecule inhibition of eIF2α dephosphorylation effectively protects cells from ER stress.” This study shows the effectiveness of salubrinal on herpes viral infections; future research is necessary to determine if it or similar compounds are effective in other diseases associated with ER stress.

Citation: Boyce M, Bryant KF, Jousse C, Long K, Harding HP, Scheuner D, Kaufman RJ, Ma D, Coen DM, Ron D, Yuan J. A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science. 2005 Feb 11;307(5711):935-9.