Discussion

Protein trafficking diseases are defined by mutant proteins, that are destined for location at the plasma membrane, but are recognized as misfolded by the cellular protein quality control systems, retained in the endoplasmic reticulum (ER), retrotranslocated into the cytoplasm where it is degraded by the proteasome. Some mutants of secretory proteins are in fact functional if they can be induced to traffic to the cell surface. One example is the F508del-CFTR mutant that, when homzygous, causes most of the cases of cystic fibrosis. Screens for correctors of trafficking of F508del-CFTR have identified molecules that allow its correct cellular trafficking. These correctors fall into two general categories. The first are “pharmacological chaperones” that bind to the mutant F508del-CFTR molecule and promote its folding so that it escapes the quality control systems. The second are “proteostasis modulators” that act on the cellular quality control systems. While the first category of correctors are specific for the mutant F508del-CFTR molecule some of the second category of proteostasis modulators can correct the trafficking of mutant proteins of other protein trafficking diseases.