Inter-organelle membrane contact sites: through a glass, darkly

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Inter-organelle membrane contact sites are zones where heterologous membranes, usually the endoplasmic reticulum plus a partner organelle, come into close apposition. These sites are very poorly understood because so few of their components have been identified; however, it is clear that they are specialised for traffic of material and information between the two membranes. There have been recent advances in the study of lipid transfer proteins, such as ceramide transfer protein (CERT) and homologues of oxysterol binding protein (OSBP). Not only can these proteins carry lipids across the cytoplasm, but they have been found to target both the endoplasmic reticulum and a partnering organelle, and in some cases have been localised to membrane contact sites. Further work will be needed to test whether these lipid transfer proteins act when anchored at inter-organelle contact sites.

Introduction

Several organelles make close contacts with each other at zones of apposition called membrane contact sites, which provide an alternative means of communication to membrane-bound carriers. Membrane contact sites are found in all organisms, from simple prokaryotes with two membranes (and hence also between the two mitochondrial membranes) to eukaryotes, where one of the partnering organelles is always the endoplasmic reticulum (ER). Since the ER network spreads into all corners of a cell, including highly asymmetric cellular projections such as neuronal dendrites, axons and synapses [1], it is not surprising that strands of the ER should be found near other organelles. For this reason, the significance of zones of very close apposition (∼10 nm) is still open to question. However, where studied, membrane contact sites are relatively stable [2] and the portion of ER involved is biochemically distinct from the bulk of the ER [3, 4]. Instead of being random, membrane contact sites are specialised for communication, in particular the efficient traffic of small molecules such as Ca2+ ions and lipids, as well as enzyme–substrate interactions occurring in trans (Figure 1a). The permanence of membrane contact sites indicates that they are structured by bridging complexes; however, only a single example demonstrates how these bridges are constructed (Figure 1b) [5].

Although no new structural components have been discovered recently, an increasing number of proteins are now known to function on two contacting organelles. This review will focus on lipid traffic, since this is often independent of NSF/Sec18-mediated vesicular traffic [6]. The hydrophobicity of lipids and the existence of lipid transfer proteins (LTPs), which reversibly bind selected lipids with 1:1 stochiometry in hydrophobic pockets, suggest that non-vesicular transport is mediated by LTPs. While it is possible that LTPs act by diffusing to-and-fro across relatively large cytoplasmic gaps, an alternative hypothesis is that LTPs are firmly attached to a membrane and yet efficiently transport lipids [7], implying that they function at a membrane contact site. Here an LTP might provide an almost static hydrophobic crossing point. Data supporting this hypothesis has been accumulating over the past few years (Figure 1c), as will be discussed below.

Section snippets

Plasma membrane–ER contacts

One organisational feature of the ER is its relationship in the cell periphery with the plasma membrane (PM). The interaction of the two organelles has been studied biochemically in only one instance, which showed the portion of ER adherent to the PM in yeast is enriched in synthases for phosphatidylserine (PS) and phosphatidylinositol (PI), lipids that are needed in the PM [4]. Several complexes bridge between the ER and the PM, although all are likely to be transient, in other words not

Golgi–ER contacts

Ultrastructural evidence shows some ER cisternae in very close contact with elements of the trans side of Golgi stacks [48], but the nature of the link is unclear. Non-vesicular lipid traffic from the ER direct to the trans-Golgi network (TGN) is documented for ceramide, being mediated by ceramide transfer protein (CERT), an LTP with targeting domains to both TGN and ER [49], similar to OSBP [32]. It has now been shown that binding to both membranes is important for the function of CERT [49]

Endosome/lysosome–ER contacts

Membrane contact sites between the ER and organelles of the endocytic pathway lie at the extremes of how clearly these structures have been defined. In budding yeast, the nucleus–vacuole junction is a membrane contact site between a portion of the ER (on the outer nuclear envelope) and the vacuole (equivalent to the lysosome). This is the sole membrane contact site whose components are known: single proteins embedded in each of the opposing membranes bind each other directly, forming

Mitochondrial–ER contacts

Organelles derived from endosymbiotic prokaryotes are not connected to the secretory pathway by vesicular traffic, and so mitochondria [50] and chloroplasts [59] acquire a large proportion of their lipids from the ER by non-vesicular routes. For mitochondria, there is considerable evidence that a specialised sub-domain of the ER, called the mitochondrial-associated membrane (MAM), adheres to mitochondria. Importantly, MAM is enriched in synthases of lipids required by mitochondria [3, 60],

Intra-mitochondrial contacts

Contacts between the outer mitochondrial membrane (OMM) and the inner mitochondrial membrane (IMM) parallel similar contacts between the two membranes of many bacteria, and have the full range of activities envisaged to occur at membrane contact sites between heterologous membranes (Figure 1a) [46, 66]. During import of cytoplasmic proteins into the mitochondrial matrix, TOM complexes on the OMM pass polypeptides directly to TIM23 complexes on the IMM. A new, conserved sub-unit of the TIM23

Conclusions

The seeds of our current understanding of vesicular traffic were sown with ground-breaking genetic and cell-free reconstitution studies that identified key components in the trafficking machine. For membrane contact sites, such discoveries are still to be made, and we remain in an earlier phase where we are still defining the very nature of the non-vesicular traffic. This article documents the increasing numbers of proteins that localise to membrane contact sites, providing candidates that

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank Anjana Roy for the use of the electron micrograph image, and we apologize to our colleagues whose work we have not been able to include because of space constraints.

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