Endoplasmic reticulum

The endoplasmic reticulum (ER) is a delicate membranous network composed of sheets and tubules that spread throughout the cytoplasm and are contiguous with the nuclear membrane. The expanded surface of the ER membrane as well as the distinct composition of the ER lumen provides a platform for various biochemical reactions, but especially for protein biosynthesis and production of lipids.

In the subcellular section, 539 genes (3% of all protein-coding human genes) have been shown to encode proteins that localize to the ER (Figure 2). Around 55% (n=297) of the ER proteins localize to other cellular compartments in addition to the ER, the most common ones being the cytosol and vesicles. A Gene Ontology (GO)-based functional enrichment analysis of the ER proteins shows enriched terms for biological processes related to protein synthesis, protein folding, protein modification, mRNA degradation and metabolic processes. Examples of ER-associated proteins can be found in Figure 1.

ASPH - A-549
STIM1 - A-549
VAPA - A-431

Figure 1. Examples of proteins localized to the endoplasmic reticulum. ASPH is an enzyme that is upregulated in human cancers (detected in A-549 cells). STIM1 is a transmembrane protein that is involved in the regulation of calcium ions (detected in A-549 cells). VAPA may regulate the morphology of the ER by interacting with the cytoskeleton (detected in A-431 cells).

Figure 2. 3% of all human protein-coding genes encode proteins localized to the endoplasmic reticulum. Each bar is clickable and gives a search result of proteins that belong to the selected category.

The structure of the endoplasmic reticulum

LRRC59 - U2OS
LRRC59 - U-251MG
LRRC59 - A-431

Figure 3. Examples of the morphology of the ER in different cell lines, represented by immunofluorescent staining of the protein encoded by LRRC59 in U2OS, U-251 MG, and A-431 cells.

The ER is a large dynamic structure (Schwarz DS et al. (2016)) made up of flat cisternal, often stacked, sheets and reticulated tubules. These are often connected by three-way junctions, which result in a polygonal pattern. The different membrane-to-lumen ratios in these two domains reflect their different functions. The sheets with their large surface are studded with ribosomes, forming the "rough ER" and is the primary location for translation of RNA into proteins. In contrast, areas in the tubules are largely devoid of ribosomes, forming the "smooth ER" and is involved in different metabolic functions and calcium homeostasis, depending on cell type (Friedman JR et al. (2011)). There are also areas that are partially smooth and partially rough, referred to as the transitional ER, where transport vesicles exit the ER on route to the Golgi apparatus.

Proteins that are suitable as markers for the ER can be found in Table 1. Highly expressed genes encoding proteins that localize to the ER are listed in Table 2.

Table 1. Selection of proteins suitable as markers for the endoplasmic reticulum.

Table 2. Highly expressed single localizing endoplasmic reticulum proteins across different cell lines.

Figure 4. 3D-view of the ER in U2OS cells, visualized by immunofluorescent staining of HSP90B1. The morphology of the ER in human induced stem cells can be seen in the Allen Cell Explorer.

The function of the endoplasmic reticulum

The ER is known to serve multiple roles in human cells (Schwarz DS et al. (2016). One of the major functions of ER is in translation of mRNA to certain groups of proteins, including secreted proteins and integral membrane proteins, but also some cytosolic proteins. Translation of these proteins is initiated in the cytosol, but the emergence of an N-terminal signal peptide leads to binding of a complex known as the Signal Recognition Particle (SRP), which then guides the nascent protein and the ribosome to SRP receptors in the rough ER. After docking to the ER, translation continues and the nascent protein gets translocated across the ER membrane through channels referred to as translocons. If a transmembrane domain is present, the protein gets incorporated in the lipid bilayer of the ER. The ER lumen contains proteins that mediate proper protein folding, post-translational modifications and quality control of the newly synthesized proteins. Proteins that are targeted for other parts of the secretory pathway, the plasma membrane or other organelles begin the process of transport from the ER, using exit sites present in the transitional ER.

Control mechanisms ensure that only correctly folded proteins are transported out of the ER. Unfolded or misfolded proteins can cause ER stress by accumulating in the lumen. This process activates the unfolded protein response (UPR), which resolves the stress by reducing the overall protein synthesis, increasing the capacity for protein folding, and promoting the removal of misfolded proteins by the ER-associated degradation (ERAD) (Travers KJ et al. (2000)). However, if the stress is not alleviated, it ultimately induces apoptosis. Several pathological processes, especially neurological diseases like Parkinson's- and Alzheimer's disease, have been linked to ER stress and an imbalance in the UPR (Roussel BD et al. (2013)).

The smooth ER contains enzymes involved in carbohydrate metabolism, gluconeogenesis, and lipid biosynthesis. The latter include synthesis of the phospholipids, which are the major lipid components of cellular membranes. In addition, the smooth ER harbours most of the cytochrome P450 enzymes that are involved in metabolism of a variety of endogenous and exogenous toxic compounds (Neve EP et al. (2010)). Moreover, the ER lumen is one of the major storage sites of intracellular calcium ions and maintains the Ca2+ homeostasis by a controlled release and uptake of the ions.

Gene Ontology (GO)-based enrichment analysis of genes encoding proteins that localize to the ER highlight several functions associated with this organelle. The most highly enriched terms for the GO domain Biological Process are related to protein translation, protein processing, mRNA degradation, biosynthesis of lipids and other metabolic processes (Figure 5a). For the GO domain Molecular Function, there is an enrichment of genes encoding protein mediating various protein modifications and controlling protein folding, as well as RNA binding proteins (Figure 5b).

Figure 5a. Gene Ontology-based enrichment analysis for the endoplasmic reticulum proteome showing the significantly enriched terms for the GO domain Biological Process. Each bar is clickable and gives a search result of proteins that belong to the selected category.

Figure 5b. Gene Ontology-based enrichment analysis for the endoplasmic reticulum proteome showing the significantly enriched terms for the GO domain Molecular Function. Each bar is clickable and gives a search result of proteins that belong to the selected category.

Endoplasmic reticulum-associated proteins with multiple locations

In the subcellular section, approximately 55% (n=297) of the annotated ER proteins also localize to other compartments in the cell. The network plot (Figure 6) shows an overrepresentation of proteins localized to the ER together with vesicles, the Golgi apparatus, the cytosol, and the nuclear membrane. Multilocalizations between the ER, the Golgi apparatus and vesicles likely reflects proteins moving within the compartments of the secretory pathway. Proteins that localize to the cytosol, can interact with the ER as part of certain functions, the most prominent example being the recruitment of ribosomal proteins to the ER. The overrepresentation of proteins localizing both to ER and and the nuclear membrane is in agreement with their continuity. On the contrary, proteins localizing to the ER and the nucleoplasm are underrepresented. Examples of multilocalizing proteins within the ER proteome can be seen in Figure 7.

Figure 6. Interactive network plot of ER proteins with multiple localizations. The numbers in the connecting nodes show the proteins that are localized to the ER and to one or more additional locations. Only connecting nodes containing more than one protein and at least 0.5% of proteins in the ER proteome are shown. The circle sizes are related to the number of proteins. The cyan colored nodes show combinations that are significantly overrepresented, while magenta colored nodes show combinations that are significantly underrepresented as compared to the probability of observing that combination based on the frequency of each annotation and a hypergeometric test (p≤0.05). Note that this calculation is only done for proteins with dual localizations. Each node is clickable and results in a list of all proteins that are found in the connected organelles.

CREB3L2 - U2OS
LPCAT2 - A-431
RPL28 - MCF-7

Figure 7. Examples for multilocalizing proteins in the endoplasmic reticulum proteome. CREB3L2 is an ER membrane protein, whose cytosolic N-terminal domain is translocated to the nucleus upon ER-stress (detected in U2OS cells). LPCAT2 is found in both the ER and lipid droplets, which agrees with role of the ER in the emergence and regression of lipid droplets (detected in A-431 cells). RPL28 encodes a component of ribosomes and is required for protein biosynthesis in both ER and cytosol (detected in U2OS cells).

Expression levels of endoplasmic reticulum proteins in tissue

Transcriptome analysis and classification of genes into tissue distribution categories (Figure 8) shows that genes encoding ER-associated proteins are more likely to be detected in all tissues, and less likely to be detected in many tissues, compared to all genes presented in the subcellular section. This indicates that a large fraction of the ER-associated proteins are likely to fulfill housekeeping functions needed in all tissue types.

Figure 8. Bar plot showing the percentage of genes in different tissue distribution categories for endoplasmic reticulum-associated protein-coding genes, compared to all genes in the Subcellular Section. Asterisk marks a statistically significant deviation (p≤0.05) in the number of genes in a category based on a binomial statistical test. Each bar is clickable and gives a search result of proteins that belong to the selected category.

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