Fig. 6

Summary: Therapeutically targeting the intracellular environment. The endoplasmic reticulum is a very important organelle for the proper folding of proteins that enter the secretory pathway. It contains stringent quality control checkpoints that monitor the folding of polypeptides and allow bone fide proteins to exit the ER and be expressed at their proper cellular localization. Research shows that proteins that are kinetically stable and thermostable in the ER, but do not conform to a proper conformation, can still progress to the secretory pathway and function similar to wild-type protein on the plasma membrane. Select therapeutic strategies are shown in red font. Pharmacological chaperones (correctors) can work at different levels of the folding cycle. Proteostasis regulators works with the ER quality control network and eliminate toxic non-native polypeptides. Fatty acyl modifications assist in proper cysteine bond formation and compact polypeptide folding. Abbreviations; ASO: antisense oligonucleotides, CRISPR/Cas9: clustered regulatory interspaced short palindromic repeats)/cas9 systems