What Role Does the Endoplasmic Reticulum Play in Cell Biology?
The endoplasmic reticulum (ER) is an extensive network of tubes and vesicles found in most eukaryotic cells. This sac-shaped organelle plays a vital role in the synthesis and transport of protein and lipid molecules, protein folding, and the metabolism of certain drugs and medicines.
Taking a Closer Look at the ER: The Smooth and the Rough
The ER has two sub-units: the rough endoplasmic reticulum (RER) and the smooth endoplasmic reticulum (SER). While they may have different structures (the RER appears like a series of flattened sacs with numerous ribosomes attached on the surface, while the SER looks more like a smooth tubular network), these two regions are usually involved in the same activities and generally share the same proteins.
The rough ER appears rough due to the ribosomes that are attached to its surface. However, these ribosomes are not permanently bound to the organelle. They only attach themselves to the binding sites (translocon) in the RER when a free ribosome translates the mRNA of a protein destined for the secretory pathway, producing a specific protein-nucleic acid.
Upon the polymerization of the amino acids, a signal peptide is formed and bound by a signal recognition particle (SRP). At this stage, translation comes to a halt and the ribosome complex binds to the translocon.
As the translation of the nascent (new) protein continues in the lumen or membrane of the rough ER, a signal peptidase removes the signal peptide and releases the ribosomes back to the cytosol. However, non-translating ribosomes may stay attached to the translocons.
The newly formed proteins are then transported to their appropriate destinations within or outside the cell through the vesicles and membrane contact sites.
The RER is prominently found in the cells of the pancreas, liver, and blood plasma and is responsible for the following:
- Protein synthesis (secreted proteins, integral membrane proteins)
- Protein folding (through the action of chaperone proteins which include protein disulfide isomerase or PDI, calnexin, calreticulin, ERp29, BiP/Grp78, and peptidylpropyl isomerase)
- N-linked glycosylation
On the other hand, the smooth ER is found mainly in the liver, ovaries, testes, and sebaceous glands. It is responsible for the production of phospholipids and cholesterol (which are crucial for the stability of the cell membrane), the metabolism of carbohydrates (which act as an energy source for the body), and the production and secretion of male and female hormones.
Moreover, the smooth ER plays a vital role in the detoxification of natural metabolism products, alcohol, and drugs, regulates the concentration of calcium ions in muscle cells, and facilitates the transport of the products synthesized in the rough ER to their appropriate destinations. With its large surface area, it also plays an integral part in the action and storage of certain enzymes and their products.
Clinical Significance: What Happens When Things Go Wrong?
When the ER stress response is activated due to viral infection, glucose deprivation, disturbances in redox and calcium regulation, or the over expression of proteins, protein folding slows down, and the number of unfolded proteins increases.
When this happens, the unfolded protein stress response (UPR) is activated in an attempt to restore normal cell function. This is usually accomplished by inhibiting protein translation, destroying misfolded proteins, and increasing the production of chaperone proteins that aid in protein folding. The chronic over-activation of the UPR has some serious implications, since it is associated with several conditions such as insulin resistance, prion disease, and other neurodegenerative diseases.
Additionally, abnormalities in X-box binding protein 1 or XBP1 (a transcription factor that regulates gene expression, angiogenesis, and plasma cell and eosinophil differentiation) may further intensify the ER stress response and increase the risk of inflammatory bowel diseases and Alzheimer’s disease.
Considering its role in disease development, researchers are looking at the possibility of developing a treatment plan for certain conditions by inhibiting the UPR.
