Complexity in targeting membrane proteins

For a cell, making hydrophobic integral membrane proteins (IMPs, or transmembrane proteins) is a complicated, but critical, process. All proteins are made by ribosomes in the cytosol, but IMPs, which account for ∼30% of the proteins encoded in the eukaryotic genome, must also be properly delivered to and inserted into their respective subcellular membranes, a process known as targeting. This is important because hydrophobic IMPs are rapidly degraded in the cytoplasm to prevent aggregation, which can lead to broad disruptions in cellular homeostasis. Because of the number and diversity of IMPs, identifying and targeting them relies on pathways that often overlap in function. The information for targeting, typically stored in hydrophobic α-helical transmembrane domain (TMD) signals in the IMPs, is recognized by factors that then ferry the IMP client to the destined lipid bilayer. On page 470 of this issue, Guna et al. ( 1 ) demonstrate that, for an essential class of IMPs, the current picture is incomplete. They identify a new targeting pathway for these IMPs, contributing to the elucidation of how the cell synthesizes this important class of proteins.