A Selective Inhibitor of eIF2α Dephosphorylation Protects Cells from ER Stress

TLDR

Most protein phosphatases lack intrinsic substrate specificity, making selective pharmacological inhibition of specific dephosphorylation reactions challenging. Salubrinal selectively inhibits eIF2α dephosphorylation, protects cells from ER stress, blocks viral‑mediated dephosphorylation and replication, and demonstrates that selective targeting of dephosphorylation is feasible and may benefit ER stress–related diseases or viral infections.

Abstract

Most protein phosphatases have little intrinsic substrate specificity, making selective pharmacological inhibition of specific dephosphorylation reactions a challenging problem. In a screen for small molecules that protect cells from endoplasmic reticulum (ER) stress, we identified salubrinal, a selective inhibitor of cellular complexes that dephosphorylate eukaryotic translation initiation factor 2 subunit alpha (eIF2alpha). Salubrinal also blocks eIF2alpha dephosphorylation mediated by a herpes simplex virus protein and inhibits viral replication. These results suggest that selective chemical inhibitors of eIF2alpha dephosphorylation may be useful in diseases involving ER stress or viral infection. More broadly, salubrinal demonstrates the feasibility of selective pharmacological targeting of cellular dephosphorylation events.