A new pharmacology–drugging stressed folding pathways

RL Wiseman, WE Balch - Trends in molecular medicine, 2005 - cell.com
RL Wiseman, WE Balch
Trends in molecular medicine, 2005cell.com
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 …
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 eIF2α. Reprogramming stress pathways with drugs provides a potential new approach for balancing ER-protein load with cellular-folding capacity, thus correcting disease.
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