Intertwined and Finely Balanced: Endoplasmic Reticulum Morphology, Dynamics, Function, and Diseases

Abstract

The endoplasmic reticulum (ER) is an organelle that is responsible for many essential subcellular processes. Interconnected narrow tubules at the periphery and thicker sheet-like regions in the perinuclear region are linked to the nuclear envelope. It is becoming apparent that the complex morphology and dynamics of the ER are linked to its function. Mutations in the proteins involved in regulating ER structure and movement are implicated in many diseases including neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS). The ER is also hijacked by pathogens to promote their replication. Bacteria such as Legionella pneumophila and Chlamydia trachomatis, as well as the Zika virus, bind to ER morphology and dynamics-regulating proteins to exploit the functions of the ER to their advantage. This review covers our understanding of ER morphology, including the functional subdomains and membrane contact sites that the organelle forms. We also focus on ER dynamics and the current efforts to quantify ER motion and discuss the diseases related to ER morphology and dynamics.

Keywords: anomalous diffusion; dynamics; dynein; endoplasmic reticulum (ER); kinesin; membrane contact site (MCS); microtubule; morphology.

Figure 1

Diagram showing the possible mechanisms of action of ER morphology-regulating proteins. (A) CLIMP-63, a transmembrane ER protein, may regulate sheet thickness by forming a dimer, linking the two bilayers of an ER sheet. (B) Lunapark locates to and stabilises three-way junctions in the ER network, although how this is achieved is not yet known. (C) Proteins promoting membrane curvature, such as the reticulon and REEP families, are shaped like hairpins and localise to tubules and sheet edges (regions of high membrane curvature). The proteins are embedded in the outer leaflet of the bilayer, with the wider end at the surface, inducing membrane curvature. (D) Static interactions between the ER and microtubules may be facilitated by CLIMP-63, p180, REEP1, and Sec61β. These proteins are all resident in the ER membrane and possess microtubule-binding domains. (E) Tip attachment complexes (TACs) are formed by interactions between the ER-resident protein STIM1 (pink) and the microtubule plus-end tracking protein EB1 (orange). (F) New tubules are fused to the network by atlastin, an ER-resident GTPase, which may reside in both of the sections of ER membrane to be fused. A dimer may be formed between the two proteins, promoting tubule fusion. Rab10, Rab18, and Drp1 may also promote tubule fusion, although the mechanisms are currently unknown. (G) Polyribosomes, groups of ribosomes gathered on the surfaces of ER sheet membranes, may maintain sheet flatness, although this has yet to be experimentally demonstrated.

Figure 2

Membrane contact site proteins that are discussed in this review. MCSs between the ER and the Golgi apparatus (A), lipid droplets (LD, (B)), the plasma membrane (PM, (C)), peroxisomes (PO, (D)), early endosomes (Endo, (E)), late endosomes/lysosomes (LE/Lyso, (G)) and mitochondria (Mito, (H)) are shown. The triple MCS between the ER, endosomes, and mitochondria is also depicted (F). Orange proteins are those known, or thought to be, involved in lipid transfer and blue proteins are calcium ion channels. Proteins with no clear function in relation to lipid or calcium ion transfer are coloured light green (transmembrane) or lilac. The dotted line in H separates MCS-forming proteins (on the left of the line) from proteins recruited to MCSs and those whose interacting partners are unknown or not included in this review. The ER–mitochondrial MCS-forming mechanisms of mitofusin 2 and REEP1 are still unclear, however, both proteins may form homodimers in order to tether the organelles [105,106].

Figure 3

Schematic depicting the dynamics of the ER network. Fluctuations of the tubules, junctions, and sheets of the ER are shown with black lines and arrows. Tubules, junctions, and sheet edges oscillate laterally (within the plane of the page) and vertically (perpendicularly to the plane of the page). Vertical sheet fluctuations, as shown by the black arrows, are also thought to occur. The transmembrane and lumenal proteins also move, as shown in the inset. Motor proteins bind to the ER and move along microtubules to draw out new tubules from the existing network (see top right).

Figure 4

Early endosomes associate dynamically with the ER. A small endosome (red and white arrows) transiently associates with the ER and extends an ER tubule (blue arrow). When released from the endosome, the ER tubule retracts. The moving endosome/ER tubule briefly interacts with another endosome (yellow arrow). Other endosomes interact statically with ER tubules (asterisks). Images of GFP Rab5 (pseudocoloured red for easier visualisation of the small vesicles) and mCherry ER marker (LongER, [20]) (cyan) were collected simultaneously at 10 fps in wide-field mode on a DeltaVision OMX (A*STAR Institute of Medical Biology, Singapore) by V. Allan. Scale bar = 2 microns.