Trends in Cell Biology
Volume 14, Issue 9, September 2004, Pages 483-490
Journal home page for Trends in Cell Biology

Short-range intracellular trafficking of small molecules across endoplasmic reticulum junctions

https://doi.org/10.1016/j.tcb.2004.07.017Get rights and content

Intracellular trafficking is not mediated exclusively by vesicles. Additional, non-vesicular mechanisms transport material, in particular small molecules such as lipids and Ca2+ ions, from one organelle to another. This transport occurs at narrow cytoplasmic gaps called membrane contact sites (MCSs), at which two organelles come into close apposition. Despite the conservation of these structures throughout evolution, little is known about this transport, largely because of a lack of knowledge of almost all molecular components of MCSs. Recently, this situation has started to change because the structural proteins that bridge an MCS are now known in a single case, and proteins implicated in lipid trafficking have been localized to MCSs. In the light of these advances, I hypothesize that the endoplasmic reticulum has a central role in the trafficking of lipids and ions by forming a network of MCSs with most other intracellular organelles.

Section snippets

Ca2+ trafficking at MCSs

Although the review will mainly present the latest findings relating to the transport of lipids, recent advances in Ca2+ transport indicate that the two processes, long held to be completely independent, might be mediated by the same cellular structures. Ca2+ is a highly bioactive cation, present at millimolar levels extracellularly, that is maintained at submicromolar concentrations in the cytoplasm of resting cells, and stored in both the ER and mitochondria. There are several instances in

Lipid trafficking in the absence of vesicular trafficking

How do lipids arrive at their correct intracellular destination? This is a particularly relevant question for organelles that do not participate in vesicular trafficking. Yet lipids are delivered efficiently from their site of synthesis, which is usually in the ER, to such organelles, including chloroplasts [14], lipid droplets [15] (Figure 2d) and, best documented of all, mitochondria. Although mitochondria can synthesize some phospholipids de novo [phosphatidic acid (PtdOH),

Non-vesicular lipid trafficking in parallel with vesicular trafficking

Organelles of the secretory pathway all have unique lipid compositions [27]. Although these differences could feasibly be mediated entirely by sorting into carrier vesicles, it has been clear for many years that there is also rapid, energy-independent transport of lipids that runs parallel to vesicular trafficking. Two clear examples of non-vesicular lipid transport within the secretory pathway, ceramide to the Golgi and PtdIns to the plasma membrane, are discussed below, and illustrate

A model for protein targeting to MCSs

One approach to establish how MCSs are built is to study how proteins are targeted to these structures. Usually, studies of intracellular targeting dissect the signals within a protein that target it to one organelle. For MCS components, the problem is more complex, as the protein targets two organelles at the same time. For this discussion, I have divided MCS components into two functional categories: structural and cargo selection. Although it is clear that structural proteins must bridge

Concluding remarks: MCSs make the ER a hub for trafficking of small molecules

The first identified MCS components tend to confirm that MCSs are involved in lipid trafficking between organelles. Targeting of a lipid-transfer protein to an MCS can be simply achieved by the presence of targeting determinants for the two different membranes. An interesting consequence of targeting both membranes simultaneously (Figure 4c) is that the lipid-transfer protein reversibly becomes a structural MCS component, that is, it can enhance the connection between the two organelles, and so

Acknowledgements

I thank Chris Loewen, Steve Moss and Sean Munro for helpful comments regarding the manuscript.

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      However, the involvements of PITPnm1 and PITPnm2 at inter-organelle membrane contact sites, and their roles at such sites in cell physiology and signaling define active topics of discussion in contemporary cell biology. Membrane contact sites (MCSs) are defined as regions within the cell where two membranes are in close (10–20 nm) apposition to each other (Friedman and Voeltz, 2011; Levine, 2004; Helle et al., 2013). There are numerous examples of these including MCSs between the ER and PM (Manford et al., 2012; West et al., 2011), and the ER and TGN (Ladinsky et al., 1999).

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