senshido.info: Cell Structure: Endoplasmic Reticulum
Cytoskeleton and Cell Membrane Physiology Curator: Larry H Bernstein, In addition to a nucleus (wherein the cell's DNA is located, and which we .. of the molecular and functional relationships between the cytoskeleton and ion .. Global Market of Medical Devices Technology (1), Global Partnering. In a cell the golgi apparatus package the cells and store them, much like the The cell membrane is similar to the entrance of the park because. The Golgi body consists of stacks of flattened membrane-enclosed and fluid-filled saccules (cisternae). Relationship with Lysosomes British Society for Cell Biology on Endoplasmic Reticulum and Golgi apparatus: . Envigo expands its bioanalytical capabilities in response to increased market demand.
A great variety of conditions and pharmacological compounds can disturb ER homeostasis, leading to ER stress and the accumulation of unfolded and misfolded proteins.
In response, ER stress signaling pathways stimulate pro-survival efforts to either neutralize the stressful insult or adapt to it.
Endoplasmic Reticulum - Wrapping it Up
In contrast, if ER stress is too severe, the pro-apoptotic module of this cellular system gains dominance and shifts the balance towards cell death. CHOP represents a central executor of this latter process. In essence, these opposing processes of cell death versus survival are reflective of the yin-yang shadow and light concept of Chinese philosophy, where seemingly contrary forces are interconnected and interdependent as part of a greater whole.
For example, the ER lumen is rich in calcium-dependent molecular chaperones, such as glucose-regulated protein 78 GRP78, also called BiP: For instance, under conditions of low glucose supply hypoglycemiaN-linked glycosylation of proteins is impaired [ 2021 ].
Imbalanced cellular redox homeostasis, which can be caused by hypoxia and prooxidant or reducing agents, interferes with disulphide bonding of proteins [ 22 ]. Aberrant calcium levels impinge on the activity of calcium-dependent chaperones [ 2324 ]. Impaired removal and degradation of terminally misfolded proteins by blocked ERAD or compromised autophagy results in the accumulation of these potentially proteotoxic proteins [ 525 — 27 ].
Viral infections may overload the ER lumen with virus-encoded proteins [ 28 — 30 ]. Key players of the ER stress system that are involved in responding to these threats to cellular homeostasis are presented in the following subsections.
As implied by its name, GRP78 initially has been characterized as a glucose-regulated protein, where restricting the availability of glucose in cell culture medium resulted in pronounced stimulation of GRP78 transcription and translation, and thus provided initial clues as to its activation during cellular stress conditions [ 3536 ].
A large number of subsequent studies established that a great variety of cellular and microenvironmental disturbances, as well as many pharmacological interventions, can lead to increased GRP78 expression, along with aggravated ER stress.
Indeed, the significantly increased amount of GRP78 protein over baseline expression has become an established indicator and marker for the presence of cellular ER stress [ 37 — 39 ]. GRP78 belongs to the heat shock protein 70 HSP70 family of proteins, where many of its members have been characterized as chaperones within the ER. In recent years, however, it was discovered that GRP78 can also be present outside the ER; for example, the protein was found in the cytosol [ 40 ], in mitochondria [ 41 ], in the nucleus [ 42 ], and at the cell surface of tumor cells [ 43 — 47 ].
It has thus emerged that GRP78, as well as a few other traditional ER-localized chaperones, can function beyond this compartment and are involved in processes not directly connected to posttranslational protein processing [ 3948 ]. Binding of GRP78 to the ER-luminal domains of these proteins keeps their activity suppressed and maintains them in an inactive state. Among the consequences of these signaling events is increased expression of GRP78, which not only serves to provide the needed additional chaperone capacity, but also eventually will reassociate with PERK, IRE1, and ATF6 in order to return these signaling modules to their inactive modes when homeostasis has been reestablished.
Upon ER stress, accumulating unfolded and misfolded proteins inside the ER sequester GRP78, thus dissociating this master regulator from all three transmembrane sensors and relieving their blockage. Activation of PERK entails homodimerization and autophosphorylation, leading to phosphorylation of eIF2which terminates global protein translation, but exempts selected ER stress-associated proteins, such as ATF4. Activation of IRE1 also entails homodimerization and autophosphorylation. ATF6 translocates to the Golgi, where it is proteolytically cleaved by S1 and S2 proteases to generate the transcriptionally active p50 fragment.
See text for further details and references. Release from suppression by GRP78 triggers its homodimerization and autophosphorylation as part of the activation process [ 52 ].
Activated IRE1 cleaves a base fragment from the mRNA encoding X box-binding protein 1 XBP1resulting in spliced XBP1s and translation of a potent transcription factor controlling the expression of genes involved in ERAD and protein folding, as well as others directing the synthesis of phospholipids that are required for the expansion of ER membranes during ER stress [ 4955 ].
IRE1 signaling and XBP1 splicing are particularly important in highly secretory cells where the protein folding machinery is continuously engaged with a high amount of nascent proteins [ 56 ]. Therefore, this branch of control serves as a key adaptive mechanism to match ER folding capacity with the demands of protein folding [ 5758 ]. In addition to splicing a number of mRNAs, a second function of IRE1 is to activate a signaling cascade involved in controlling cell fate with regard to cell death.
On one hand, sustained JNK activity during prolonged ER stress inhibits antiapoptotic members of the Bcl-2 B cell lymphoma 2 family of proteins. Combined, these events lead to oligomerization of Bax and Bak, resulting in permeabilization of the outer mitochondrial membrane and execution of the intrinsic apoptotic process [ 586162 ] see Figure 3. In case of severe and sustained ER stress, a number of proapoptotic events begin to dominate and lead to apoptosis.
On the other hand, CHOP inhibits antiapoptotic proteins of the Bcl-2 family and stimulates pro-apoptotic Bim, altogether leading to heterodimerization and activation of pro-apoptotic Bax and Bak. CHOP also stimulates expression of cell surface death receptor DR5, which sensitizes cells to pro-apoptotic stimuli, presumably via calibrating the extrinsic apoptotic pathway involving caspase Calcium release from the ER via IP3 receptors can activate calpains, which further stimulate caspase 12 activation via proteolytic cleavage of its inactive procaspase precursor.
Here, it is proteolytically cleaved by Golgi-resident site-1 protease S1P, a serine-protease in its ER luminal domain and by site-2 protease S2P, a metalloprotease within its region that spans the Golgi phospholipid bilayer, resulting in the release of the cytosolic bZIP transcription factor domain from the Golgi membrane [ 63 ]. Besides ATF6, a number of other ER-transmembrane bZIP transcription factors have been described in recent years that are also regulated by intramembrane proteolysis.
In contrast to ubiquitous ATF6, expression of these factors appears to be tissue specific to variable degrees. It has been surmised that these variant proteins perhaps respond to tissue-specific conditions of ER stress that may require tissue-specific gene expression patterns to resolve that stress [ 31 ].
Phosphorylation of eIF2 attenuates global protein synthesis, thereby decreasing protein influx to the ER in support of resolving the cytotoxic threat from accumulated misfolded proteins [ 68 ]. At the same time, phosphorylation of eIF2 changes the efficiency of AUG initiation codon usage and leads to the preferential translation of a small number of mRNAs, including activating transcription factor 4 ATF4a transcription factor that stimulates a set of genes involved in supporting recovery and adaptation [ 50 ].
Among ATF4-regulated genes is the one encoding CHOP, a key transcription factor that is important to initiate the apoptotic program in case of excessive ER stress [ 69 ] see details in next subsection. Upon activation, this basic-leucine zipper transcription factor migrates to the nucleus where it activates genes encoding antioxidant proteins and detoxifying enzymes [ 70 ].
Because ER stress may involve the accumulation of reactive oxygen species ROSthereby promoting a state of oxidative stress, Nrf2 plays a critical role in fighting such perturbations in redox homeostasis [ 71 ]. The importance of this defensive role of Nrf2 has been further emphasized by findings that Nrf2-deficient cells displayed greatly increased cell death following exposure to ER stress [ 72 ]. The full proapoptotic effect of CHOP only emerges when ER stress cannot be subdued by the efforts of the prosurvival module of the response system, and the levels of misfolded proteins remain high.
In this case, CHOP stimulates a transcriptional profile that facilitates a pro-apoptotic program. It includes expression of proapoptotic Bim and repression of antiapoptotic Bcl-2 [ 7576 ], which represents a mechanism that is aligned with similar pro-apoptotic efforts of JNK mentioned previously see Figure 3and detailed refs.
Endoplasmic reticulum and Golgi bodies (video) | Khan Academy
As well, CHOP induces death receptor 5 DR5which further sensitizes cells to apoptotic stimulation by a variety of conditions that cause ER stress [ 78 ]. Thus, while sustained elevation of CHOP expression triggers strong pro-apoptotic signaling, its initial effect on GADD34 may contribute to the restoration of homeostasis—with the caveat that the renewed supply of client proteins to the ER, if taking place too early, that is, under conditions where ER stress is not yet completely resolved, can trigger the generation of reactive oxygen species ROS with deleterious consequences for cell survival [ 77 ].
In any case, the dissolution of ER stress entails mandatory suppression of CHOP levels as a prerequisite for return to homeostasis [ 81 ]. However, if these countermeasures prove unsuccessful and severe imbalances persist, the response system abandons its prosurvival efforts and instead initiates proapoptotic mechanisms that gain dominance and eventually will lead to cell death.
Because of these dichotomic efforts between cell survival and cell death, the ER stress response mechanisms can be viewed as a cellular display of yin-yang principles, where the two opposing forces of cell death and survival balance each other for the greater good of ensuring survival of the organism as a whole Figure 1. GRP78, the previously introduced master regulator of the ER stress response, represents the perhaps most critical proponent of the prosurvival yang module of this system.
As mentioned, GRP78 protein is key in activating the response system in an initial effort to pursue adaptation and cellular survival. Even more so, the robust pro-survival potency of this protein provides significant growth advantage to tumor cells and endows them with the ability to withstand and even thrive under otherwise adverse microenvironmental conditions, such as hypoglycemia and hypoxia that is common within tumor regions with insufficient blood supply.
Worse for a patient with cancer, chronically elevated expression of GRP78 in tumor tissue may provide resistance to chemotherapy and may spell worse prognosis [ 82 — 86 ]. Both proteins exert significant pro-apoptotic efforts in a variety of ways, central among them the suppression of important antiapoptotic proteins and the stimulation of pro-apoptotic components [ 6987 ] Figure 3. The relevance of IRE1-mediated JNK activation for ER stress-induced cell death has been highlighted by experiments where the activity of this module was blocked with small molecule inhibitors or the use of knockout cell lines [ 59698788 ].
In unstressed cells, CHOP protein levels generally are below detection levels, but are substantially increased upon acute ER stress. In fact, the presence of conspicuous amounts of CHOP protein represents a marker for the acute phase of the activated ER stress response. Prolonged, high-level expression of CHOP indicates that the ER stress response system has exceeded the limits of its protective yang capacity and that it has switched to its pro-apoptotic yin module—despite the continued presence of elevated GRP78 [ 6981 ].
Conversely, during moderately intense short-term stress, or when the cell is adapting to longer-lasting chronic stress, efforts of the pro-survival yang module include the suppression of CHOP expression as a prerequisite for recovery and survival, which entails reassociation of GRP78 with and inactivation of the ER transmembrane signaling components PERK, IRE1, and ATF6 [ 819394 ].
For this reason, both proteins are convenient and indeed frequently used markers to distinguish between the chronic and acute phases of ER stress [ 819195 ]. Targeting ER Stress for Therapy As presented in greater detail later, the activated ER stress response system has been found involved in a number of human diseases and therefore is being recognized as an emerging target for therapy see Table 1.
In accordance with the previously described yin-yang principle of this cellular system, two conceptually opposing approaches are offered in order to therapeutically target ER stress.
Table 2 shows a list of compounds with inherent potency to ameliorate ER stress and minimize its apoptotic consequences. Human diseases linked to ER stress. Compounds with potency to ameliorate ER stress.
On the other hand, efforts to further aggravate preexisting ER stress and enhance pro-apoptotic processes could be beneficial in the case of malignant neoplasms. Both rough ER and smooth ER have the same types of membranes but they have different shapes.
Rough ER looks like sheets or disks of bumpy membranes while smooth ER looks more like tubes. Rough ER is called rough because it has ribosomes attached to its surface. The double membranes of smooth and rough ER form sacs called cisternae.
When enough proteins have been synthesized, they collect and are pinched off in vesicles.
The vesicles often move to the Golgi apparatus for additional protein packaging and distribution. It is important in the creation and storage of lipids and steroids. Steroids are a type of ringed organic molecule used for many purposes in an organism. They are not always about building the muscle mass of a weight lifter. This is the cell. This right over here is the cytosol of the cell. And you might be sometimes confused with the term cytosol and cytoplasm.
Cytosol is all the fluid between the organelles. Cytoplasm is everything that's inside the cell. So it's the cytosol and the organelles and the stuff inside the organelles is the cytoplasm. So cytoplasm is everything inside of the cell. Cytosol is just the fluid that's between the organelles. So anyway, the free ribosome over here, this translation is good for proteins used within the cell itself.
The proteins can then float around the cytosol and used in whichever way is appropriate. But how do you get protein outside of the cell, or even inside the cellular membrane? Not within it, within the cell, but embedded in the cell membrane or outside of the cell itself. And we know that cells communicate in all sorts of different ways and they produce proteins for other cells or for use in the bloodstream, or whatever it might be.
And that's what we're going to focus on in this video. So contiguous with this what's called a perinuclear space right over here, so the space between these two membranes-- So you have this perinuclear space between the inner and outer nuclear membrane. Let me just label that. That's the inner nuclear membrane.
That's the outer nuclear membrane. You could continue this outer nuclear membrane, and you get into these kind of flaps and folds and bulges. And this right over here is considered a separate organelle. So you get this thing that looks like this, and I'll just do it the best that I can draw it. And this right over here is called the endoplasmic reticulum. So this right here is endoplasmic reticulum, which I've always thought would be a good name for a band.
And the endoplasmic reticulum is key for starting to produce and then later on package proteins that are either embedded in the cellular membrane or used outside of the cell itself.
So how does that happen? Well, the endoplasmic reticulum really has two regions. It has the rough endoplasmic reticulum. And the rough endoplasmic reticulum has a bunch of ribosomes. So that's a free ribosome right over here.
endoplasmic reticulum | Definition, Function, & Location | senshido.info
This is an attached ribosome. These are ribosomes that are attached to the membrane of the endoplasmic reticulum. So this region where you have attached ribosomes right over here, that is the rough endoplasmic reticulum. I'll call it the rough ER for short. Perhaps an even better name for a band. And then there's another region, which is the smooth endoplasmic reticulum. And the role that this plays in protein synthesis, or at least getting proteins ready for the outside of the cell, is you can have messenger RNA-- let me do that in that lighter green color-- you can have messenger RNA find one of these ribosomes associated with the rough endoplasmic reticulum.
And as the protein is translated, it won't be translated inside the cytosol. It'll be translated on the other side of the rough endoplasmic reticulum.
Or you could say on the inside of it, in the lumen of the rough endoplasmic reticulum. Let me make that a little bit-- let me draw that a little bit better.