Polar transmembrane domains target proteins to the interior of the yeast vacuole

Membrane proteins transported to the yeast vacuole can have two fates. Some reach the outer vacuolar membrane, whereas others enter internal vesicles, which form in late endosomes, and are ultimately degraded. The vacuolar SN AREs Nyv1p and Vam3p avoid this fate by using the AP-3-dependent pathway, w hich bypasses late endosomes, but: the endosomal SNARE Pep12p must avoid it more directly. Deletion analysis revealed no cytoplasmic sequences necessa ry to prevent the internalization of Pep12p in endosomes. However, introduc tion of acidic residues into the cytoplasmic half of the transmembrane doma in created a dominant internalization signal. Ln other contexts, this same feature diverted proteins from the Golgi to endosomes and slowed their exit from the endoplasmic reticulum. The more modestly polar transmembrane doma ins of Sec12p and Ufe1p, which normally serve to hold these proteins in the endoplasmic reticulum, also cause Pep12p to be internalized, as does that of the vacuolar protein Cps1p. It seems that quality control mechanisms rec ognize polar transmembrane domains at multiple points in the secretory and endocytic pathways and in endosomes sort proteins for subsequent destructio n in the vacuole. These mechanisms may minimize the damaging effects of abn ormally exposed polar residues while being exploited for the localization o f some normal proteins.