Intertwined And Finely Balanced: Endoplasmic Reticulum Morphology, Dynamics, Function, And Diseases Part 1

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. 

The endoplasmic reticulum is an important organelle in cells. It is mainly involved in cell synthesis, processing, secretion, and other processes. Although the endoplasmic reticulum and memory do not seem to be directly related, they are indeed closely related in some aspects.

First, the endoplasmic reticulum is involved in the synthesis and function of brain cells. Therefore, the endoplasmic reticulum plays an indispensable role in the normal development and function of brain cells. The development and function of brain cells are closely related to human memory, which means that there is also a connection between the endoplasmic reticulum and memory.

Second, in the brain, the endoplasmic reticulum is associated with synaptic plasticity. The formation and maintenance of memory are closely related to synaptic plasticity. The endoplasmic reticulum is also involved in the generation and release of many neurotransmitters during the synthesis, processing, and secretion of proteins within cells. These neurotransmitters are related to synaptic plasticity. Therefore, the endoplasmic reticulum can also affect memory.

In addition, the endoplasmic reticulum also participates in the metabolic process of brain cells and maintains normal metabolic levels of cells. Abnormalities in the endoplasmic reticulum may affect the physiological functions of brain cells, which may also affect advanced cognitive functions such as memory. Therefore, maintaining the normal function of the endoplasmic reticulum plays an important role in maintaining and improving brain health and cognitive function.

To sum up, there is indeed a connection between the endoplasmic reticulum and memory, and this connection is not negative. Therefore, in daily life, to maintain brain health and improve memory, we should pay attention to the normal function and metabolic level of the endoplasmic reticulum, so that we can better maintain our own health and cognitive functions. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory because Cistanche deserticola is a traditional Chinese medicinal material that has many unique effects, one of which is to improve memory. The efficacy of Cistanche deserticola comes from the multiple active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc. These ingredients can promote brain health through a variety of pathways.

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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: 

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

1. Introduction

The endoplasmic reticulum (ER) is a subcellular organelle responsible for a variety of essential cellular functions. In the ER, proteins are synthesized and undergo posttranslational modification, calcium ions are stored and released as dictated by cellular signaling, and lipids are biosynthesis. 

The ER is the largest organelle in the cell and extends as a continuous membrane-bound entity from the nuclear envelope to the cell periphery in a complex network of tubules and sheet-like regions. Fast dynamics and re-organization, along with the fact that the ER comprises ~35% of the cytoplasmic volume, mean that the ER explores the volume of the cytoplasm more rapidly than any other organelle [1]. 

Little is understood as of yet about the function of ER dynamics or the effects of dynamics in ER-related diseases. The complex structure of the ER is maintained by a variety of proteins including reticulons, REEPs, and atlastins [2–4]. These morphology-regulating proteins promote membrane curvature [2,3], drive tubule fusion [4–8], stabilize junctions [9–11], regulate sheet spacing [12–14], and tether the ER to microtubules [15–17]. 

Cooperation between these proteins is essential for normal morphology, with overexpression of certain types leading to abnormal proportions of sheets and tubules in the network [6,9,18]. The microtubule motor proteins kinesin-1 and cytoplasmic dynein (referred to herein as dynein) also bind to the endoplasmic reticulum to drive the formation of new tubules and to continuously and dynamically remodel the network (e.g., [19,20]). 

Interactions between the ER and other organelles at membrane contact sites (MCSs) also contribute to the dynamics of the organelle (Section 3.1.2). ER dynamics is an emerging topic of research. 

Historically, tubule extension speeds have been measured [20–23], but the quantification of other aspects of ER dynamics has been challenging due to limitations in microscopy and computation. Recently, software designed to analyze the motion of the ER in live cells has been published [24–27] and further developments in this area are likely shortly. 

Although the relationship between ER dynamics and function is not yet understood, abnormal ER dynamics have recently been linked to several diseases [8,28,29], indicating that dynamics are likely to be very important. In contrast, disease-related mutations in morphology-regulating proteins are rather better understood and links between morphology and function have been established [30,31]. 

This review will detail the current understanding of ER morphology, dynamics, and function and the interplay between them, as well as the diseases linked to abnormalities in morphology and dynamics, focussing primarily on the ER in vertebrate cells. Section 2 will describe ER morphology, the proteins involved in maintaining normal ER structure, and the links between morphology and function that have been elucidated. 

Section 3 will describe the dynamics of the ER, factors causing organelle motion, current efforts to quantify the dynamics, and recent developments in computational analysis and modeling. 

Finally, Section 4 will detail the known links between ER structure/motion and diseases as well as the proteins involved in these diseases. A discussion of the subdomain organization of the ER specifically in neuronal cells is presented in another article of this special issue [32].

2. Morphology

A lipid bilayer bounds the lumen of the ER. This bilayer is formed into sheets and tubules of roughly 80–100 nm diameter [25,33,34], with a range of ~50–100 nm [33], which are connected at junctions to form a reticular network. 

Tubules are around 1 µm in length on average and connect at junctions, usually joining 3 tubules [27,35]. The sheets are flat, with a bilayer separation of 30–50 nm [33], and often occur in a stacked configuration with helical ramps connecting the layers [36]. 

Sheet density is usually higher nearer the center of the cell (e.g., [33,37,38]), where the endoplasmic reticulum also includes the nuclear envelope; however, sheet-like regions also occur in peripheral ER. 

Super-resolution light microscopy has revealed that some peripheral structures originally thought to be sheets consist of dense matrices of tubules [33,34,38], while others comprise sheets fenestrated with tiny holes (nanoholes: [33]). 

Research into the proteins involved in shaping the ER membrane is extensive and has been reviewed recently [30,31,39]. The complex morphology of the ER has recently been linked to its function (reviewed in [40]) and can be changed in response to altered metabolic requirements or cell cycle stages, as described later.

2.1. Morphology-Regulating Proteins

A plethora of proteins are involved in regulating ER morphology. These proteins stabilize high membrane curvature regions, promote membrane fusion, maintain threeway junctions, regulate sheet thickness and flatness, and anchor the ER to microtubules (Figure 1). 

ER, tubules, and sheet edges are regions of high membrane curvature. The hairpin-like REEP and reticulon protein families promote curvature in the surface of the ER to stabilize tubules and sheet edges [2,3]. 

Reticulon 4 also accumulates at the edges of nanoholes, which are absent in Rtn4 knockout cells [33]. These proteins are thought to sit with the wider end of the 'hairpin' at the outer edge of the membrane to promote curvature via hydrophobic wedging, as shown in Figure 1C. Membrane fusion is also essential to maintain correct ER morphology. Atlastin, an ER-resident GTPase, is required for ER network maintenance and membrane fusion [4–6]. 

New tubules that are drawn out from the existing membranous structure must be fused to the network to preserve normal ER morphology. Bian et al. proposed that atlastin is resident in the membrane of both of the uniting edges and that a dimer is formed between the two proteins [41] (see Figure 1F). This dimerization would cause a conformational change in which the proteins, and therefore the ER membrane, would be pulled closer together, eventually causing membrane fusion. 

Two RabGTPases, Rab10 [7], and Rab18 [8] have also been implicated in ER tubule fusion. Depletion of either of these proteins caused an increase in sheets and a decrease in tubules. 

Rab10 also localizes to the growing tips of ER tubules that are enriched in two lipid synthesis enzymes: phosphoinositol synthase (PIS) and CEPT1 [7]. Interestingly, dynamin-related protein 1 (Drp1), a protein required for mitochondrial fission, has been shown to promote ER tubule formation independently of Rtn4 [42].

The three-way junctions of the ER network in mammalian cells are stabilized by mammalian Lnp1, a member of the Lunapark family [9–11]. mLnp1 localizes to threeway junctions in Cos-7 cells, and junctions lacking in mLnp1 were much more dynamic and shorter-lived than their mLnp1-enriched counterparts [10]. 

Lunapark-free junctions frequently disappeared by ring closure, in which junctions slide along a neighboring tubule until they coalesce with another junction, whereas ring closure was less common for mLnp1 junctions [10]. 

Therefore, Lunapark stabilizes three-way junctions in the network. The cooperation of these proteins is crucial in ER morphology regulation. To maintain normal ER morphology, a balance between reticulon 4a and atlastin expression was required [6]. Long, unbranched tubules were seen in cells with little atlastin function and in cells overexpressing reticulon 4a. 

Both atlastin and reticulon 4a expression in Lunapark knockout cells restored normal network morphology at the cell periphery. In yeast, a balance between the Lunapark Lnp1p and the atlastin homolog Sey1p is required for typical polygonal network formation [9]. Lunapark and atlastin also coordinate to form and maintain three-way junctions in mammalian cells, with Lunapark unable to localize to junctions when atlastins are deleted [18]. 

Using a different but complementary approach, Shemesh et al. modeled the ER network, focusing on two classes of morphology-regulating proteins [43], with Lunapark being proposed to be a negative curvature-inducing protein and reticulons enhancing straight edges. Altering the expression level of Lunapark in Cos-7 cells gave rise to different ER morphologies, and various network properties such as the total length and the preferred shape of junctions were replicated by changing protein concentrations in the simulations. 

The relative concentrations of the ER morphology-regulating proteins are of great importance for normal ER structure. CLIMP-63, an integral membrane protein, has been suggested as a mechanism for controlling the lumenal separation between the two membranes of ER sheets [12–14]. As shown in Figure 1A, its large coiled-coil domain sits within the lumen of the ER and has been hypothesized to bind to the coiled-coil domains of other CLIMP-63 proteins to regulate sheet thickness [12]. Over-expression of CLIMP-63 induces the formation of sheets containing nanoholes [33]. 

The second factor influencing sheet thickness may be groups of ribosomes, also called polyribosomes, bound to the cytosolic face of the ER [44] (see Figure 1G). Removing ribosomes from the ER surface converted sheets to tubules, supporting the hypothesis that polyribosomes stabilise ER sheets [45]. p180 and kinectin, two proteins that are similar in conformation to CLIMP-63, may play a role in flattening the surface of sheets [13], although there is little conclusive evidence supporting this idea. Both proteins are potential receptors for the microtubule motor kinesin-1 (see Section 3.1.1). 

Microtubules and the actin cytoskeleton play a major role in regulating ER position and morphology, both via dynamic and static links (Figure 1D, E), as discussed in Section 3. Together, the proteins involved in cytoskeletal binding and motility, membrane curvature stabilization, tubule fusion, junction maintenance, and sheet thickness regulation are essential for the maintenance of normal ER structure.

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