Intertwined And Finely Balanced: Endoplasmic Reticulum Morphology, Dynamics, Function, And Diseases Part 2

2.2. Structural and Functional ER Subdomains

Different structural domains of the ER, which are responsible for specific functions, have been hypothesized since the first electron microscopy images of the ER were obtained. 

The relationship between structural domains and memory is one of the important topics in studying memory. Structural domains refer to areas in the brain responsible for different functions, such as visual structural domains, auditory structural domains, etc. Because different structural domains correspond to different sensory information, their processing methods and storage rules in the brain are also different, which will affect the formation and maintenance of memory.

Research has found that information in different structural domains is stored in the brain at specific times and then encoded, stored, and retrieved. For example, auditory information needs to be memorized immediately, while visual information can be memorized delayed. This shows that information in different structural domains has different memory characteristics and requires different memory strategies to be memorized.

In addition, there are interactions between different structural domains. Research shows that visual and auditory information can complement each other to enhance memory. For example, when learning a word, observing its appearance and pronunciation can be stored in the brain at the same time, which can increase the memory amount and quality of the word.

Research has also found that emotions can influence the formation and retention of memories. The emotional structure domain and the memory structure domain in the brain are interconnected. The ups and downs of emotions will affect the signal transmission and information processing in the brain, thereby affecting the formation and maintenance of memory.

Therefore, to improve memory, we need to understand the relationship between different structural domains, adopt corresponding memory strategies, and also maintain a good emotional state. Through active learning and lifestyle, we can continuously improve our memory capabilities and make our brains healthier and stronger. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche deserticola can also promote the growth and repair of nerve cells, thus enhancing the connectivity and function of neural networks. These effects can help improve memory, learning, and thinking speed, and may also prevent the development of cognitive dysfunction and neurodegenerative diseases.

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In the 1950s, it was noticed by George E. Palade that ER sheets tended to be studded with ribosomes, known as rough ER, whereas tubules were largely ribosome-free, or smooth [46,47]. This difference in structure in different regions of the network sparked the hypothesis of ER functional subdomains. Since then, significant work has been undertaken to correlate the morphology of the ER with its function.

2.2.1. Protein Factory and Quality Control

The best-understood role of the ER is to synthesize and insert proteins into the ER membrane or lumen, and this happens primarily by ribosomes associating with the cytosolic face of the ER, where the newly synthesized polypeptide chain is translocated through the Sec61 translocon, as reviewed in this special issue by Sicking et al. [48]. 

In S. Cerevisiae, sheet ribosome density was found to be significantly larger than tubule ribosome density [49]. As ribosomes attach to the ER to allow the translation of secreted or membrane-bound proteins, this result, along with the results of electron microscopy studies such as those by Palade [46,47], led to the idea that sheets are the main site for protein biosynthesis in the ER. The relatively low membrane curvature and large lumenal volume of sheets are optimal for both the binding of ribosomes or polyribosomes to the bilayer and for the accessibility of chaperones to nascent peptides needed for folding and post-translational modifications. 

In agreement with the idea that ribosome-studded sheets of rough ER form a "protein factory" functional domain, cells that are specialized in secreting proteins, such as pancreatic secretory cells, have a higher proportion of ER sheets than cells that secrete very few proteins, such as epithelial cells and neurons [50]. Components of the translocon were also enriched in sheets [13]. 

Taken together, these results strongly suggest that sheets are the primary location of protein biosynthesis in the ER. Newly synthesized membrane and lumenal proteins need to fold properly and be appropriately modified post-translationally, for example by the addition and subsequent trimming of glycan chains and the formation of disulfide bridges (reviewed in [51,52]). 

This process involves multiple ER-resident chaperones and enzymes that act in sequence to assist and monitor the correct folding and glycosylation status through the calnexin/calreticulin cycle. Any proteins that fail to fold are recognized and removed from this cycle, to be retrotranslocation out of the ER and degraded by the proteasome in a process termed ER-associated degradation (ERAD) [51]. 

The load of misfolded proteins is closely monitored, and if too many build up, the unfolded protein response (UPR) is triggered, which leads to upregulation of the key ER-resident proteins required for protein folding combined with inhibition in protein synthesis [53]. 

While the proteins involved in folding and glycan addition are ubiquitously distributed throughout the ER, there is evidence that certain key proteins in the quality control and ERAD pathways may be concentrated in specialized structures called the ER-derived quality control compartment (ERQC) which is localized next to the nucleus [52]. While the exact nature of this compartment and how it is connected to the bulk ER remains unclear, its localization depends on the microtubule motor dynein [54]. 

Interestingly, prolonged ER stress has been seen to induce the reversible formation of whorls of ribosome-free ER membranes that contained the Sec61 translocon and the key UPR signaling enzyme PKR-like ER kinase (PERK), but not reticulons, CLIMP63 or the lumenal marker calreticulin [55]. The whorls formed from vesicular/tubular structures that budded from the ER via the COPII pathway (see below) and subsequently fused and flattened. This is markedly different from normal conditions, where Sec61 is excluded from COPII vesicles. 

These whorls may facilitate two UPR outcomes: inhibition of protein translocation by segregating and inactivating translocons, and activation of PERK. The whorls resemble the organized smooth ER (OSER) previously seen when certain ER proteins such as HMG-CoA reductase or cytochrome b5 are over-expressed [56,57]. How whorls and OSER relate to the ERQC is a key question to be addressed in the future.

2.2.2. ERES: Export Checks

Correctly folded lumenal and membrane proteins leave the ER at ER exit sites (ERES), which are structurally distinct, ribosome-free puncta located in the rough ER network. 

Exit sites consist of a cluster of vesicular-tubular membranes [58,59], continuous with the ER membrane. In vertebrate cells, ERES are scattered throughout the network, and protein transfer from the ER to the Golgi relies on microtubule-dependent transport via the dynein/dynactin motor protein complex [60]. The ERES themselves undergo short-range movements on microtubules [61]. 

Two protein coat complexes, COPI and COPII, aid in the formation and organization of the exit sites as well as in protein transport. COPII forms a scaffold to deform the membrane, regulates cargo entry into ERES [62], and remains localized to ERES even after cargoes have departed [63–65]. COPI however, travels with the cargo as it is transported away from exit sites [66], as does Rab1 [65]. The exact roles of COPI in cargo trafficking away from the ER are unknown, but it may play a role in sorting and delivering cargo to the Golgi apparatus [66,67]. 

The higher-order structure of ERES has only recently been identified using FIB-SEM. Weigel et al. discovered that an interwoven network of narrow tubules (40–60 nm in diameter) exists at exit sites, connected to the ER by a slightly narrower COPII neck [63]. Long, pearling tubules with COPI punctae were also found to extend from the exit sites, along microtubules towards the Golgi apparatus. 

Pearled outlines are a hallmark of longitudinal tension in tubular membranes [68] and may be the result of forces applied by dynein/dynactin [60]. Such membrane pearling has been hypothesized as a precursor to fission, transforming tubules into vesicles [69]. 

Dynein may be recruited to ERES membranes via an interaction between dynactin p150 and the COPII components Sec23 and Sec24 [70], but how the motor attaches to carriers once the coat is lost is an open question. One potential route is via BicD2 and Rab6, which have been shown to recruit dynein to ERES and drive their concentration in the perinuclear region [59]. 

Kinesin-1 is also present on both ERES [61] and the transport carriers they produce [71]. Interestingly, exit sites were also found to double in diameter in response to the accumulation of cargo, while the diameter of nearby ER tubules was unaffected [63]. Together, these studies show that ER exit sites are highly organized cargo export subdomains, capable of responding to changes in cell requirements.

2.2.3. MCSs: Lipid Manufacture

Given that sheets are likely to be responsible for protein biosynthesis, could tubules be responsible for lipid synthesis and calcium ion homeostasis? In support of this idea, cells responsible for steroid synthesis, such as adrenal cortical cells, have proportionally more ribosome-free smooth ER [72]. 

It has also been suggested that membrane contact sites (MCSs) between the ER and other organelles may be more common in the ribosome-free tubular region of the network, particularly those MCSs formed with the plasma membrane, endosomes, lipid droplets, and mitochondria [73–78]. The MCSs and relevant proteins discussed in this review are shown in Figure 2. 

MCSs are tethered connections between organelles, where the membranes are not fused, but separated by 5–30 nm [79–82]. Such proximity of the membranes enables the non-vesicular transfer of cargo between the organelles [83]. MCSs are present between the ER and almost every other subcellular organelle [38,81]. Their function, morphology, and dynamics are diverse and well-reviewed (e.g., [84–86]). 

Here, we will focus on the links between MCSs and ER function and dynamics. Lipid biosynthesis is known to occur primarily in the ER [87,88]. Using cell fractionation, enrichment of the machinery involved in lipid and sterol synthesis was discovered in the ER membrane that is associated with mitochondria [89–91] and the plasma membrane [92]. 

More recently, it has been shown that ER–plasma membrane contact sites are required for the synthesis of phosphatidylcholine, an integral component of biological membranes, in yeast [93]. Lipid metabolizing machinery has also been found at the leading edge of dynamic ER tubules [7] and in dynamic ER-derived vesicles that contact many other organelles in Cos-7 cells [94]. 

The ER is also responsible for the synthesis of neutral lipids [95]. Neutral lipids lack charged groups and therefore cannot easily be integrated into lipid bilayers. Instead, lipid droplets are formed, which consist of a phospholipid monolayer surrounding a core of neutral lipids. Exact details about the formation of lipid droplets are still up for debate; however, it is now known that lipid droplets are formed in the ER [96–98]. 

Neutral lipids gather within the lipid bilayer of the ER, forming a lens between the inner and outer leaflets [97], before budding off into the cytoplasm [99]. In plants, it has also been suggested that lipid droplets are formed in specialized subdomains of the ER [100]. I

n addition to being formed in the ER, lipid droplets can re-contact the ER once they have budded off [101]. The ER–lipid droplet membrane bridges formed are proposed to facilitate the exchange of lipid metabolizing enzymes, without which large lipid droplets are not formed [102–104]. 

The discovery of upregulated lipid metabolizing machinery in the tubular ER, particularly at MCSs with the plasma membrane, mitochondria, and lipid droplets, suggests that these subdomains also participate in lipid metabolism [7,89–92,94,95].

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