The endoplasmic reticulum

The endoplasmic reticulum (ER) is a multi-functional organelle vital for the proper functioning of a cell. It consists of the rough ER (rER), which serves as a site for the synthesis, folding, and transport of proteins, and the smooth ER (sER), which is heavily involved in the biogenesis of lipids and steroids (Schwarz and Blower, 2015). When folded correctly, a protein’s cellular function occurs normally; however, the accumulation of unfolded or incorrectly folded proteins during stressed conditions in the ER leads to the instigation of the unfolded protein response (UPR). This aims to protect the cell from a cellular stress response known as ER stress, which coordinates adaptive and apoptotic responses in order to restore and maintain ER homeostasis (Boyce and Yuan, 2006). The pathogenesis of disease states such as neurodegenerative diseases, metabolic disorders, type II diabetes, and inflammatory diseases, however, have also been linked to prolonged and persistent ER stress (Ozcan and Tabas, 2012).
The ER is crucial in the process of producing proteins, playing a vital role in protein folding. According to a (2015) study conducted by Schwarz et al., the localisation of ribosomes to the cytosolic face of a healthy, properly-functioning ER allows for the synthesis of correctly-folded, operational proteins. As well, the co-translational attachment of the messenger RNA (mRNA) ribosomal complex to the membrane of the ER allows for the canonical pathway involved in the regulation of protein synthesis. It is in the cytosol that the translation of secretory or integral membrane proteins commences, and the ER where the translation continues. Via a sequence of signals that occurs within the amino terminus of the nascent polypeptide bound by the signal recognition particle (SRP), ribosomes containing the mRNAs from the protein translations in the cytosol are sent to the membrane of the ER. The complex formed from the binding of the mRNA ribosome, nascent polypeptide, which is derived from the ribosome-nascent chain complex (RNC), and SRP is sent to the ER where it binds to the SRP receptor. Upon the completion of the translation process occurring in the ER, the emerging polypeptide is able to co-translationally enter the ER via the translocon, which spans the lipid bilayer and acts as a channel containing several Sec proteins. The protein must finally undergo proper folding and modifications through the interactions between the cytosolic regions of transmembrane proteins and chaperones, resulting in correctly-folded, functional proteins for cellular use.
ER stress is caused primarily by the accumulation of aberrant polypeptides. The lumen of the ER acts as a major site for the proper folding of proteins, containing molecular chaperones and several folding enzymes (Ozcan et al., 2012). Proteins that have been properly folded are exported to the Golgi apparatus, whilst those that have been incompletely folded are retained in the ER to either complete the folding process or to be delivered into the cytosol to undergo ER-associated degradation. An equilibrium is established between the protein load of the ER and its folding capacity under physiological conditions; however, due to potentially increased rates of protein synthesis or accumulation of incorrectly-folded proteins leading to alterations in ER homeostasis, a condition known as ER stress can arise (Ozcan et al., 2012). In order to effectively deal with this stress, an adaptive signalling pathway (called the UPR) has been developed by cells to alleviate ER stress and thus re-establish homeostasis (Ma, 2008). This can be accomplished via two mechanisms: increasing the folding capacity of proteins through the expression of protein-folding chaperones, or down-regulating the protein load of the ER through the inhibition of general protein translation and promoting of the degradation of misfolded or aggregated proteins (Ozcan et al., 2012). Prolonged or sever stress can, however, cause the initiation of apoptosis by the UPR, contributing to the onset of several disease states.
Upon activation by ER stress, the most evolutionarily conserved UPR signalling pathway in mammalian cells, kinase/endoribonuclease inositol-requiring enzyme-1 (IRE1), results in the excision of a fragment from the mRNA encoding the transcription factor X-box-binding protein-1 (XBP1) (Kaser et al., 2008). This produces XBP1s, required for the expansion of the ER and the development of secretory cells, such as pancreatic epithelial cells and plasma cells. Intestinal epithelial cells (IECs) also express IRE1?, the deletion of which causes increased ER stress, as well as exacerbated dextran sodium sulfate (DSS)-induced colitis, an inflammatory disease (Kaser et al., 2008).
According to a (2008) study conducted by Arthur Kaser, Ann-Hwee Lee, Andre Franke, Jonathon N. Glickman, Sebastian Zeissig, Herbert Tilg, Edward E.S. Nieuwenhuis, Darren E. Higgins, Stefan Schreiber, Laurie H. Glimcher, and Richard S. Blumberg, the ER stress links to intestinal inflammation by XBP1 in cells with secretory activity was investigated. In the experiment, XBP1 mice were bred with Villin (V)-Cre transgenic mice (within whom the mouse villin 1 promoter directs the expression of Cre recombinase), and the newborn offspring allowed to develop normally. The deletion of the XBP1 exon 2 within the intestinal epithelium illustrated elevated basal GRP78 (an ER chaperone and signalling regulator) levels in XBP1, signifying increased ER stress within the small intestinal epithelia. 61% of adult XBP1 mice demonstrated spontaneous small intestinal mucosal inflammation, associated with elevated ER stress, ad 31% of the heterozygous offspring mice displayed mild spontaneous small intestinal inflammation. The results obtained from the study highlight the inability of XBP1-deficient IECs to appropriately respond to inflammatory signals. Furthermore, numerous single nucleotide polymorphisms (SNPs) located within the XBP1 gene locus demonstrate a vulnerability to Inflammatory Bowel Disease (IBD), illuminating the ER stress pathway as a genetic contributor to inflammatory diseases within the human population.
The ER is a major site for protein synthesis, a process that is heavily mediated to ensure the correct folding and modification of proteins. The accumulation of aberrant polypeptides, however, instigates ER stress, which, through various studies conducted, such as the 2008 study conducted by Kaser et al., illustrates a strong link to the onset of inflammatory diseases such as IBD.