In this review, Gomez-Navarro and Miller summarize the principles of cargo sorting by the vesicle traffic machinery and consider the diverse mechanisms by which cargo proteins are selected and captured into different transport vesicles.

Cells possess multiple mechanisms that protect against the accumulation of toxic aggregation-prone proteins. Here, we identify a pre-emptive pathway that reduces synthesis of membrane proteins that have failed to properly assemble in the endoplasmic reticulum (ER). We show that loss of the ER membrane complex (EMC) or mutation of the Sec61 translocon causes reduced synthesis of misfolded forms of the yeast ABC transporter Yor1. Synthesis defects are rescued by various ribosomal mutations, as well as by reducing cellular ribosome abundance. Genetic and biochemical evidence point to a ribosome-associated quality-control pathway triggered by ribosome collisions when membrane domain insertion and/or folding fails. In support of this model, translation initiation also contributes to synthesis defects, likely by modulating ribosome abundance on the message. Examination of translation efficiency across the yeast membrane proteome revealed that polytopic membrane proteins have relatively low ribosome abundance, providing evidence for translational tuning to balance protein synthesis and folding. We propose that by modulating translation rates of poorly folded proteins, cells can pre-emptively protect themselves from potentially toxic aberrant transmembrane proteins.

Approximately one third of a cell's proteins are destined to function outside the cell's boundaries or while embedded within cellular membranes. Ensuring these proteins reach their diverse final destinations with temporal and spatial accuracy is essential for cellular physiology. In eukaryotes, a set of interconnected organelles form the secretory pathway, which encompasses the terrain that these proteins must navigate on their journey from their site of synthesis on the ribosome to their final destinations. Traffic of proteins within the secretory pathway is directed by cargo-bearing vesicles that transport proteins from one compartment to another. Key steps in vesicle-mediated trafficking include recruitment of specific cargo proteins, which must collect locally where a vesicle forms, and release of an appropriate cargo-containing vessel from the donor organelle (Figure 1). The newly formed vesicle can passively diffuse across the cytoplasm, or can catch a ride on the cytoskeleton to travel directionally. Once the vesicle arrives at its precise destination, the membrane of the carrier merges with the destination membrane to deliver its cargo.