A new pharmacology - drugging stressed folding pathways

Folding in the endoplasmic reticulum (ER) must couple protein-synthesis pathways operating outside of the compartment with ER-assisted folding (ERAF) pathways in the lumen. Chaperone-mediated folding imbalances that are associated with numerous misfolding diseases, including diabetes, trigger the unfolded-protein response (UPR), using both transcriptional and translational pathways to correct the problem. Recent work suggests that small-molecule inhibitors could be useful to help rebalance protein synthesis with ERAF pathways through the ribosomal initiating factor eIF2 alpha. Reprogramming stress pathways with drugs provides a. potential new approach for balancing ER-protein load with cellular-folding capacity, thus correcting disease.