In eukaryotic cells, the modification and folding of membrane and secreted proteins occurs in the endoplasmic reticulum (ER). Agents that interfere with these processes cause such proteins to accumulate in the ER, leading to ER stress. Geoff Werstuck and colleagues now show that valproate, a branched-chain fatty acid used to treat epilepsy, protects cells from the lipid accumulation and apoptosis associated with ER stress (see ). The authors report that, although valproate increases the expression of ER chaperones in the human hepatic cell line HepG2, it does not directly protect these cells from ER stress by increasing protein folding capacity. Instead, valproate protects the ER from the cellular complications induced by stress by inhibiting glycogen synthase kinase 3 (GSK3). Other GSK3 inhibitors have similar effects, indicating that GSK3 plays a central role in the cellular responses to ER stress. Thus, small-molecule drugs that inhibit GSK3 could provide new treatments for disorders in which ER dysfunction is implicated, including Alzheimer's disease and type-1 diabetes mellitus.
