Chaperones for membrane protein biosynthesis and quality control

A substantial proportion of the genome encodes membrane proteins that are delivered to the endoplasmic reticulum by dedicated targeting pathways. We have been investigating the mechanisms by which membrane proteins are targeted through the cytosol en route to the membrane. We are discovering that the cytosol contains a set of chaperones that are dedicated to binding the highly hydrophobic domains that characterize membrane proteins. Unexpectedly, these chaperones appear to serve a dual purpose. In addition to directing membrane protein targeting, they also recruit ubiquitin ligases that can mediate substrate ubiquitination. This dual functionality ensures rapid degradation of membrane proteins that fail to be properly localized. Such a system may be important for preventing the aggregation of especially hydrophobic mislocalized membrane proteins, thereby maintaining protein folding homeostasis in the cytosol.