Nearly all the molecules that are expressed in mammalian cells reach their correct intracellular locations by virtue of sophisticated transport-and-delivery systems. Central among these is the intracellular membrane-transport apparatus, which is designed to ferry most of the transmembrane proteins and nearly all the secreted proteins — about a third of the human proteome — from their site of synthesis, the endoplasmic reticulum, to their final destinations.

Membrane transport is responsible for controlling the size, shape, and molecular composition of most cellular organelles, including the plasma membrane, and for mediating the secretion of thousands of cargo species, including hormones, growth factors, antibodies, matrix and serum proteins, digestive enzymes, and many more. To carry out this enormous task, the system relies on a large ensemble of organelles, including the endoplasmic reticulum, the Golgi complex, and the endolysosomal stations, and on an underlying molecular machinery that is estimated to comprise more than 2000 proteins. It is no surprise, then, that alterations to membrane transport, either genetic or otherwise, are associated with many diseases. Here, after a brief overview of the pathways, strategies, and mechanisms of membrane transport, we focus on mendelian disorders that arise from defects of the membrane-transport machinery.

Pathways of Membrane Trafficking

The main morphologic and functional features of the secretory and endocytic pathways were initially sketched out by the pioneers of modern cell biology in the 1960s and 1970s. Since then, this picture has grown enormously in richness and complexity, and the underlying molecular machinery has been unraveled through approaches that are based on yeast genetics and biochemical identification of the relevant components in mammals.

The transport of newly synthesized secretory proteins begins at their site of synthesis, the endoplasmic reticulum, a network of dynamically interconnected membrane tubules and cisternae.

Proteins are cotranslationally inserted into the lumen of the endoplasmic reticulum, where they are glycosylated and folded by a complex machinery that includes the chaperone proteins. Folding is essential, and when it cannot be completed, proteins are degraded by the degradation system associated with the endoplasmic reticulum. Moreover, if unfolded proteins accumulate in the endoplasmic reticulum, as they do under certain stress conditions, the unfolded-protein response ensues. The unfolded-protein response is a compensatory reaction that results primarily in an increase in the production of the folding-machinery proteins but can also influence different cell functions and lead to cell death or survival.

After folding, proteins enter the exit sites of the endoplasmic reticulum, where they are sorted into either small or large pleomorphic budding vesicles that are generated through the membrane-bending properties of coat protein complex II (COPII). All vesicles then detach from the endoplasmic reticulum through membrane fission and move to the endoplasmic reticulum–Golgi intermediate compartment (ERGIC). From there, carriers containing secretory cargoes are transported forward to the Golgi complex. This step requires another coat complex, COPI, and includes the translocation of the carriers along microtubules mediated by motor proteins. From the cis pole of the Golgi, the secretory cargoes proceed toward the trans pole, whereas the machinery proteins that participate in the formation of anterograde carriers must be returned to the endoplasmic reticulum for another round of transport. This recycling is the task of COPI-dependent vesicles that form from both the ERGIC and the Golgi complex.