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 eIF2alpha. Reprogramming stress pathways with drugs provides a potential new approach for balancing ER-protein load with cellular-folding capacity, thus correcting disease.
Wiseman
R Luke
RL
Department of Chemistry and The Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd, MB-6, La Jolla, CA 92037, USA.
Balch
William E
WE
D000818:Animals; D002934:Cinnamates / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects*; D017510:Protein Folding; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*
D002934:Cinnamates; D014157:Transcription Factors; C496827:salubrinal; C101003:ELF2 protein, human; D013890:Thiourea