Homeostatic control of the endoplasmic reticulum (ER) both as the site for protein handling (synthesis, folding, trafficking, disaggregation and degradation) and as a Ca2+ store is of crucial importance for correct functioning of the cell. Disturbance of the homeostatic control mechanisms leads to a vast array of severe pathologies. The Ca2+ content of the ER is a dynamic equilibrium between active uptake via Ca2+ pumps and Ca2+ release by a number of highly regulated Ca2+-release channels. Regulation of the Ca2+-release channels is very complex and several mechanisms are still poorly understood or controversial. There is increasing evidence that a number of unrelated proteins, either by themselves or in association with other Ca2+ channels, can provide additional Ca2+-leak pathways. The ER is a dynamic organelle and changes in its size and components have been described, either as a result of (de)differentiation processes affecting the secretory capacity of cells, or as a result of adaptation mechanisms to diverse stress conditions such as the unfolded protein response and autophagy. In this review we want to give an overview of the current knowledge of the (short-term) regulatory mechanisms that affect Ca2+-release and Ca2+-leak pathways and of the (long-term) adaptations in ER size and capacity. Understanding of the consequences of these mechanisms for cellular Ca2+ signaling could provide a huge therapeutic potential.
"The ER has an essential role in folding secretory and cellular proteins during their transit, and ER chaperone proteins avert the toxic buildup of incorrectly folded secretory proteins. In addition to this critical role in protein folding, quality control, and targeting, the ER is also involved in the synthesis of a wide range of cellular lipids   along with regulation of Ca 2+ homeostasis . Any malfunction in ER can lead to cell death by activating a series of ER chaperones that participate in the regulation of protein folding and the induction of cell death . "
[Show abstract][Hide abstract] ABSTRACT: Even though endoplasmic reticulum (ER) stress associated with mycobacterial infection has been well studied, the molecular basis of ER as a crucial organelle to determine the fate of Mtb is yet to be established. Here, we have studied the ability of Mtb to manipulate the ultrastructural architecture of macrophage ER and found that the ER-phenotypes associated with virulent (H37Rv) and avirulent (H37Ra) strains were different: a rough ER (RER) with the former against a smooth ER (SER) with the later. Further, the functional attributes of these changes were probed by MS-based quantitative proteomics (133 ER proteins) and lipidomics (8 phospholipids). Our omics approaches not only revealed the host pathogen cross-talk but also emphasized how precisely Mtb uses proteins and lipids in combination to give rise to characteristic ER-phenotypes. H37Ra-infected macrophages increased the cytosolic Ca2+ levels by attenuating the ATP2A2 protein and simultaneous induction of PC/PE expression to facilitate apoptosis. However, H37Rv inhibited apoptosis and further controlled the expression of EST-1 and AMRP proteins to disturb cholesterol homeostasis resulting in sustained infection. This approach offers the potential to decipher the specific roles of ER in understanding the cell biology of mycobacterial infection with special reference to the impact of host response.
"These data highlight the importance of avoiding increased activity of RyR because ER Ca 2+ leak clearly favors the development of dysfunctional ␤ cells and endothelial cells . Translocons are protein-conducting channels in the surface of the rough ER . In pancreatic acinar cells and LNCaP prostate cancer cells it has been shown that puromycin, an antibiotic capable of purging translocons off nascent polypeptide chains, induces a large reduction of ER [Ca 2+ ] L  . "
[Show abstract][Hide abstract] ABSTRACT: The endoplasmic reticulum is the main intracellular Ca2+ store for Ca2+ release during cell signaling. There are different strategies to avoid ER Ca2+ depletion. Release channels utilize first Ca2+-bound to proteins and this minimizes the reduction of the free luminal [Ca2+]. However, if release channels stay open after exhaustion of Ca2+-bound to proteins, then the reduction of the free luminal ER [Ca2+] (via STIM proteins) activates Ca2+ entry at the plasma membrane to restore the ER Ca2+ load, which will work provided that SERCA pump is active. Nevertheless, there are several noxious conditions that result in decreased activity of the SERCA pump such as oxidative stress, inflammatory cytokines, and saturated fatty acids, among others. These conditions result in a deficient restoration of the ER [Ca2+] and lead to the ER stress response that should facilitate recovery of the ER. However, if the stressful condition persists then ER stress ends up triggering cell death and the ensuing degenerative process leads to diverse pathologies. Particularly insulin resistance, diabetes and several of the complications associated with diabetes. This scenario suggests that limiting ER stress should decrease the incidence of diabetes and the mobility and mortality associated with this illness.
"ER functions majorly in translocating and integrating proteins (secretory and membrane proteins respectively), assisting their folding and transport (extracellular or to cell membrane), lipid biosynthesis, and maintaining calcium homeostasis. It is also a site for post translational modification (N -linked glycosylation) of proteins and is considered as a signaling organelle (Berridge, 2002; Fagone and Jackowski, 2009; Sammels et al., 2010; Braakman and Bulleid, 2011). Ribosomes embedded on rough endoplasmic reticulum (RER) are sites for protein synthesis and secretion. "
[Show abstract][Hide abstract] ABSTRACT: Execution of fundamental cellular functions demands regulated protein folding homeostasis. Endoplasmic reticulum (ER) is an active organelle existing to implement this function by folding and modifying secretory and membrane proteins. Loss of protein folding homeostasis is central to various diseases and budding evidences suggest ER stress as being a major contributor in the development or pathology of a diseased state besides other cellular stresses. The trigger for diseases may be diverse but, inflammation and/or ER stress may be basic mechanisms increasing the severity or complicating the condition of the disease. Chronic ER stress and activation of the unfolded-protein response (UPR) through endogenous or exogenous insults may result in impaired calcium and redox homeostasis, oxidative stress via protein overload thereby also influencing vital mitochondrial functions. Calcium released from the ER augments the production of mitochondrial Reactive Oxygen Species (ROS). Toxic accumulation of ROS within ER and mitochondria disturbs fundamental organelle functions. Sustained ER stress is known to potentially elicit inflammatory responses via UPR pathways. Additionally, ROS generated through inflammation or mitochondrial dysfunction could accelerate ER malfunction. Dysfunctional UPR pathways have been associated with a wide range of diseases including several neurodegenerative diseases, stroke, metabolic disorders, cancer, inflammatory disease, diabetes mellitus, cardiovascular disease, and others. In this review, we have discussed the UPR signaling pathways, and networking between ER stress-induced inflammatory pathways, oxidative stress, and mitochondrial signaling events, which further induce or exacerbate ER stress.
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