Thus, a conspicuous feature of the mammalian transport apparatus is its great complexity. There are more transport strategies, types of vesicles, and trafficking pathways than was expected until only a few years ago. Also, each anterograde trafficking step is counterbalanced by one or more recycling steps, and most of the various endocytic stations appear to be interconnected bidirectionally.31 Moreover, certain specialized cells host uniquely differentiated organelles (e.g., secretory granules in endocrine and exocrine cells, melanosomes in melanocytes, lytic granules in immune cells, and dense granules in platelets), and at least in some cells (and potentially in all) there are unconventional secretion pathways through which a number of soluble cytosolic proteins can be transported directly to the extracellular space and some transmembrane proteins can be transported to the cell surface without passing through the Golgi complex32.

A consequence of this multiplicity is a remarkable degree of redundancy and functional plasticity of the transport systems. This redundancy can partially compensate for certain genetic defects, and it can do so more efficiently in some cells than in others, depending on cell-specific requirements, which results in the selective vulnerability of certain tissues.

Another important issue is how the overall trafficking system maintains its homeostasis in the face of the rapid membrane fluxes that constantly change the size and composition of the transport organelles, or compartments. Among several possible mechanisms, one that has been recently explored relies on signaling circuits located on the trafficking organelles themselves that sense the passage of traffic and rapidly react to restore the balance across the compartments.

Mechanistic Basis

During the past decade, the increasingly rapid discovery of genes that are linked to human diseases has revealed that several such genes are involved in membrane trafficking. Efforts are now being more specifically directed toward understanding how disease manifestations can be mechanistically explained through our basic knowledge of the trafficking machinery and toward exploiting this new knowledge of the molecular basis of genetic syndromes to obtain insights into the organization of the trafficking processes.

Mendelian diseases of membrane trafficking arise from mutations in genes that encode either cargo proteins or components of the biosynthetic and trafficking machinery. Among these genes, those that encode cargo proteins are more widely represented because they are more numerous and because many cargoes are tissue-specific and not essential for the survival of an embryo. On the other hand, mutations in genes that encode ubiquitous transport-machinery proteins are more likely to be lethal. Nevertheless, several of these mutations have been found to be involved in mendelian diseases, and more continue to be reported. Probably some of these mutations can, under favorable conditions, be partially compensated for by the plasticity of the transport systems.