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Structure and function of ER membrane contact sites with other organelles

Key Points

  • The endoplasmic reticulum (ER) forms tight membrane contact sites (MCSs) with several organelles in animal cells and yeast. The function of MCSs between the ER and mitochondria and endosomes are summarized in this Review.

  • Electron microscopy studies reveal that although MCSs are less than 30 nm apart, the membranes do not fuse and each organelle maintains its identity. Ribosomes are excluded from the ER membrane at MCSs, and the distance between the ER and other membranes is close enough to suggest that the two organelles are tethered together by other proteins located on apposing membranes.

  • Live-cell fluorescence microscopy reveals that ER-organelle MCSs can remain stable while both organelles traffic through the cell on the cytoskeleton. Recently identified factors have been shown to regulate organelle trafficking through MCS formation.

  • ER–organelle MCSs regulate the lipid environment of the organelle membrane apposed to the ER. Lipid-synthesis proteins on the ER can modify lipids on the membrane of another organelle or on protein complexes. ER MCS may also transfer lipids between membranes.

  • ER–organelle MCSs are sites of dynamic Ca2+ crosstalk. Organelles can sequester Ca2+ released from the ER, which can regulate processes in these organelles. Additionally, ER Ca2+ release may regulate protein complexes at ER MCS.

  • Mitochondria and endosomes undergo fission and fusion to, respectively, maintain their integrity and properly sort signalling receptors in the cell. ER–organelle MCSs define the position of fission for both mitochondria and endosomes, and the ER could have a variety of roles at those specific MCSs that are destined for fission.

Abstract

The endoplasmic reticulum (ER) is the largest organelle in the cell, and its functions have been studied for decades. The past several years have provided novel insights into the existence of distinct domains between the ER and other organelles, known as membrane contact sites (MCSs). At these contact sites, organelle membranes are closely apposed and tethered, but do not fuse. Here, various protein complexes can work in concert to perform specialized functions such as binding, sensing and transferring molecules, as well as engaging in organelle biogenesis and dynamics. This Review describes the structure and functions of MCSs, primarily focusing on contacts of the ER with mitochondria and endosomes.

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Figure 1: Structure of endoplasmic reticulum (ER) membrane-contact sites (MCSs).
Figure 2: Dynamics of endoplasmic reticulum (ER) membrane contact sites (MCSs).
Figure 3: Endoplasmic reticulum (ER) membrane contact sites (MCSs) function in lipid biosynthesis and exchange.
Figure 4: Calcium (Ca2+) exchange at endoplasmic reticulum (ER) membrane contact sites (MCSs).
Figure 5: Endoplasmic reticulum (ER) membrane contact sites (MCSs) define the timing and position of both mitochondrial and endosome fission.

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Acknowledgements

The authors thank Matt West, Jonathan Friedman, Jason Lee, Ashley Rowland and Patrick Chitwood for images used here, and Laura Westrate for comments on the manuscript. This work was supported by grants from the American Cancer Society and from the U.S. National Institutes of Health (NIH) (GM083977) to G.K.V.. M.J.P. was supported by a U.S. National Science Foundation (NSF) Graduate Research Fellowship (DGE 1144083) and by a pre-doctoral training grant from the NIH (T32 GM08759).

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Correspondence to Gia K. Voeltz.

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Glossary

Peripheral ER

The ER network that spans from the perinuclear region of the cell to the cell periphery.

ER sliding

ER tubules attach to a motor protein on a stable microtubule. The motor protein then pulls the ER tubule along the microtubule.

Early endosomes

Endosomes that have been recently internalized into cells and labelled with RAB5 GTPase, have a relatively low pH, and have not further internalized cargo, such as signalling receptors, from the plasma membrane into intraluminal vesicles.

Late endosomes

Mature endosomes that have not yet fused with the lysosome. These endosomes are labelled with RAB7 GTPase, have a relatively high pH, and have abundant intraluminal vesicles internalized into the lumen for easier degradation of cargo when the late endosome fuses with the lysosome.

Cortical ER

Peripheral ER that is found directly underneath and tethered to the plasma membrane.

Microsomes

ER vesicles resulting from the breakage of the ER network as the ER is isolated from cells.

Nucleoid

Mitochondrial DNA associated with proteins that compact into one region of the mitochondrion.

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Phillips, M., Voeltz, G. Structure and function of ER membrane contact sites with other organelles. Nat Rev Mol Cell Biol 17, 69–82 (2016). https://doi.org/10.1038/nrm.2015.8

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