Membrane trafficking

Camillo Golgi was the first to glimpse the endomembrane system when he observed what we now refer to as the Golgi apparatus in silver stained neuronal tissue (Golgi, 1898). It would take nearly fifty years and the adoption of the electron microscope before the endoplasmic reticulum was revealed (Porter, Claude and Fullam, 1945) and it was only after the revelation of the ER that the function of the ER/Golgi became apparent when a combination of techniques including pulse chase experiments and cell fractionation demonstrated the role of the ER/Golgi in the production and targeting of secreted proteins (see the contemporary reviews by de Duve, 1975; Palade, 1975). However, to understand the role of the ER/Golgi in protein trafficking at the molecular level numerous advances would be required. Importantly though, Singer and Nicholson's model of the lipid bilayer provided a growing molecular appreciation of the structure of biological membranes (Singer and Nicholson, 1972) and the first structural studies of membrane proteins (Henderson and Unwin. 1975; Deisenhofer et al., 1985) produced a framework for considering how transmembrane proteins involved in trafficking might be organised at the molecular level.

Currently the challenge is to understand how the proteins that enter the endomembrane system, including transmembrane and luminal proteins (estimated at over 25 percent of the proteins encoded by the human genome (Small et al., 2004)) are sorted and targeted; which brings us to the thematic review papers in this issue.

Katy Routledge, Vijay Gupta and William Balch have reviewed the role of the ER in preparing nascent proteins produced by ER bound ribosomes for trafficking. Newly synthesised proteins must be appropriately folded requiring a battery of proteins and the interaction of this process of protein maturation with the subsequent packaging of exported proteins into COPII coated vesicles is considered both in health and disease. This theme is continued by Katy Schmidt and David Stephens who emphasise the wide range of cargos that must be selectively loaded into COPII vesicles and the potential mechanisms involved in this process. Mutations of proteins involved in cargo loading are associated with a number of human diseases, which are also discussed here. In addition, Taku Tamura, Johan Sunryd and Daniel Hebert examine what is known concerning the quality control evaluation machinery of the ER and what happens to those proteins that fail to mature appropriately within the ER.

The role of coat proteins in protein sorting is reviewed by Mathieu Pinot, Bruno Goud and Jean-Baptiste Manneville. In particular they concentrate on the role of COPI proteins in orchestrating the movement of material from the Golgi to the ER and within the Golgi stacks and that theme is developed by Mihaela Anitei, Thomas Wassmer, Christoph Stange and Bernard Hoflack who examine the machinery involved in coordinating membrane traffic between the trans-Golgi network and the endosomal system.

Suzanne Pfeffer and Frank Brown explore the recent advances in the understanding of vesicle tethering. The review concentrates on the mechanisms by which tethers initiate the interaction between transport vesicles and their target membranes and their potential role in regulating the targeting process. Insights into the tethering mechanism from an analysis of structural information are also discussed.

Although understandably most of the research effort in this area has been directed at understanding vesicular trafficking, lipid droplets in the cytoplasm are also trafficked. This neglected organelle has an important role and defects in the trafficking of this organelle are associated with a number of diseases. Fariba Kalantari, John Bergeron and Tommy Nilsson analyse the data for the proteome of this distinctive organelle. They have evaluated competing theories for the formation of these lipid droplets and discuss the potential role of COPI and COPII in lipid droplet formation. They suggest a mechanism for the partitioning of SNARE proteins into lipid droplets formed in this way.

Finally Marek Elias provides an overview of current thinking concerning the evolutionary origins of the eukaryote endomembrane system. The revealing of the core endomembrane machinery (established before the last eukaryotic common ancestor) using phylogenomic and comparative genomic approaches provides a frame work for understanding the complexity and wide variation demonstrated by the endomembrane systems of modern eukaryotes.