Get(3)-ting tail-anchored proteins sorted

Tail-anchored membrane proteins exhibit strongly hydrophobic segments embedded in the membrane, and to avoid the aggregation of these segments before membrane insertion, they are targeted to membranes post-translationally. Their secretion involves a cascade of proteins, which cooperates in a conserved pathway to accept the newly synthesised tail-anchored proteins from ribosomes, guiding them to a receptor at the endoplasmic reticulum (ER) where membrane integration takes place. An important component of the GET-pathway is the ATPase Get3, which shuttles the target protein through the cytosol. The conformation of Get3, and thus its ability to interact with tail-anchored proteins, is controlled by its nucleotide state. However, it is not known how the GET pathway reacts to energy depletion, which might prevent membrane insertion and result in the accumulation of hydrophobic proteins in the cytosol. Now, Blanche Schwappach and colleagues (p. 473) analyzed the localisation of Get3–GFP foci under different conditions of cellular stresses that perturb membrane insertion. They find that under conditions of energy depletion, such as glucose starvation, Get3 has a second function as an ATP-independent holdase that makes use of its chaperone activity to bind hydrophobic protein segments. Moreover, they show that Get3 moves to deposition sites for protein aggregates, and thereby supports the sequestration of tail-anchored proteins when membrane insertion is inhibited, suggesting that the GET pathway acts as a quality control platform in cellular proteostasis.