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In support of the hypothesis that mitosis-specific phosphorylation of ER-shaping proteins regulates ER remodeling during mitosis two studies have examined this phenomenon in detail. A study of the ER sheet promoting protein Climp63 [ 51 ] has demonstrated mitosis-specific phosphorylation on three N-terminal residues [ ].
Phosphorylation of Climp63 blocks the interaction of Climp63 with microtubules. Additionally, phosphomimetic mutants blocked the interaction of the ER with microtubules during interphase and resulted in an ER composed primarily of sheets, while nonphosphorylatable mutants tethered the ER to microtubules and resulted in an extremely distorted ER. These results suggest that mitotic phosphorylation of Climp63 likely blocks the interaction of the ER with microtubules and could be an important step in the tubule-to-sheet transition that occurs during mitosis.
A second study examined the interaction of the ER with growing microtubule plus ends during mitosis. However, during mitosis the ER is excluded from the mitotic spindle and does not exhibit plus tip growth events.
A recent study [ ] has demonstrated that STIM1 is specifically phosphorylated during mitosis to control the interaction of the ER with microtubules. Clearly much more work remains before we have a clear understanding of how cell cycle signaling cascades contribute to reshaping of the mitotic ER. While the above studies demonstrated that phosphorylation of key proteins that link the ER to the microtubule cytoskeleton is important for excluding the ER from the spindle during mitosis a recent study demonstrated the importance of an interaction of the ER with microtubules for clearing the ER from mitotic chromatin.
During mitosis the nuclear envelope is absorbed into the ER and is cleared from the surface of the chromatin, however little is known about the mechanisms that regulate ER removal from the chromatin. Taken together these three studies demonstrate that interaction of the ER with microtubules is a major mechanism that contributes to shape rearrangement during mitosis and that ER:microtubule interactions are regulated by mitotic phosphorylation.
In addition, these studies demonstrate that the ER interacts with microtubules using many different adaptor proteins and that these different adaptor proteins serve different functions during mitosis. One of the greatest changes during development occurs at fertilization. As in mitosis, the transition from oocyte to embryo requires many coordinated cellular changes including release from meiotic arrest, resumption of mitosis, fusion of pronuclei, activation of signaling cascades and changes in protein expression [ — ].
In order for development to proceed normally, the egg must undergo the proper calcium response in order to initiate the developmental program and embryogenesis [ ]. While the exact mechanism and conformational changes vary slightly among all organisms studied, the ER architecture in oocytes of all animals changes including Xenopus [ , ], sea urchin [ ], starfish [ ] and mouse [ ]. Initial studies in starfish oocytes revealed that the ER is comprised of interconnected sheets of membranes, though following germinal vesicle breakdown GVBD , the ER sheets wrap around yolk platelets resembling a shell [ ].
In immature mouse oocytes, large clusters were found deep within the cytoplasm [ ]. Following GVBD, the spindle and surrounding ER migrate to the cortex leading to another round of ER reorganization into vegetally localized clusters in the metaphase II egg in addition to a finer reticular network throughout the egg [ , ]. Interestingly, these steps are dependent on the microtubule network as nocodazole and inhibition of cytoplasmic dynein both prevent the ER reorganization [ ].
Formation of the ER clusters is prevented by the depolymerization of microfilaments, but not microtubules [ ]. Given the timing of each of these reorganizations, it seems likely that they are related to increases in cyclinB:cdk1 activity that occurs upon oocyte maturation [ ].
These observations show an additional time in development where the ER and microtubule network interact to regulate ER structure. In Xenopus immature oocytes, the network in both the animal pigmented half and vegetal unpigemented half appears to be uniform and consists of tubules and individual, unstacked sheets [ ]. Additionally, the vegetal half contains annulate lamellae, stacks of sheets with membranes containing densely packed nuclear pores [ ].
In mature eggs, the ER in the animal half is unchanged, however the annulate lamellae in the vegetal half disappeared. Interestingly, it has been proposed that the annulate lamellae share many properties with the nuclear envelope [ ]. In place of the annulate lamellae dense, irregularly shaped ER clusters were present. The appearance of these clusters coincided with germinal vesicle breakdown.
These clusters disappeared and reappeared throughout maturation and upon fertilization dispersed and permanently disappeared. The reorganization of the ER is coupled to the cell cycle as the clusters present in mature eggs contain IP 3 receptors [ ] and release calcium from IP 3 channels at fertilization [ , ]. Along with these changes comes a transient intracellular calcium wave, initiated during sperm entry, released from the ER and extracellular stores [ 40 , 42 , — ].
There is one major difference in eggs of mice versus eggs of frogs. Frogs, as well as sea urchin [ ] and starfish [ , ] have a single calcium transient at fertilization [ ]. Other animals, including mice and humans, have multiple smaller calcium transients following fertilization, and these differences may be reflected in the ER organization in mature eggs [ ]. Mice [ ] and frogs display ER clusters that are similar in size and location the side opposite the meiotic spindle and possess IP 3 receptors [ , ].
However, fertilization in mice occurs on the side with the ER clusters whereas fertilization in frogs occurs in the animal pole where the meiotic spindle is located. Therefore, the clusters may be involved in secondary calcium wave propagation. The organization of the ER network, and the reorganization throughout oogenesis, serves as a functional consequence of calcium signaling and propagation in these organisms [ ].
We currently do not know much about the molecular mechanisms that lead to changes in ER shape during meiotic maturation and fertilization, and this should be a major are of research interest. As seen so far, the ER is an organelle of many different functions that must be tightly regulated to carry out the proper functions.
One of the most prominent functions of the ER is protein synthesis. Even with several chaperones and folding enzymes in place, an accumulation of unfolded or misfolded proteins in the lumen of the ER can occur. When the cell undergoes this type of stress there are several things that must occur to retain balance and proper function, including translational inhibition, degradation of unfolded or misfolded proteins, and an increase in the production of chaperones and folding enzymes to restore normal function of the ER and the cell.
If the balance is not restored it can lead to cell death or apoptosis [ ], therefore achieving normal function is critical to the survival of the cell. As discussed above, once a peptide destined for secretion has entered the lumen of the cell, there are several modifications that occur, including N-linked glycosylation, disulfide bond formation and oligomerization [ 3 ]. N-linked glycosylation can occur co-translationally as the protein is translocated into the ER lumen.
Misfolding can occur due to the unique environment of the lumen and the high protein concentration of both newly synthesized proteins, proteins ready for secretion and proteins that act as molecular chaperones and folding enzymes.
Logistically, due to the high protein concentration and packing in the lumen, the folding enzymes must first identify and find the proper target protein for folding to take place. If proteins are not modified correctly, the lack of glucose residues is recognized by the ER and proteins including UDP-glucose:glycoprotein glucosyltransferase UGGT in an attempt to re-glycosylate the protein [ — ].
If the normal folding process is not restored, hydrophobic residues are exposed and bound by Grp78, accumulation of these proteins occurs and the unfolded protein response UPR is activated [ , ]. The first action of the UPR is to increase ER abundance to accommodate the needs of the cell to properly fold the proteins, leading to an expansion of the ER through the generation of sheets [ ] and an increase in the ER folding machinery.
Briefly, activation of these pathways lead to production of b-ZIP transcription factors that activate UPR genes [ ]. First, ER-resident IRE1, a transmembrane endoribonuclease, mediates the post-transcriptional, non-canonical splicing of XBP1 mRNA that is localized to the ER [ — ] and encodes a transcription factor involved in upregulating additional stress response genes. The cell has evolved this mechanism to reduce the translational load on the ER by removing mRNAs that otherwise would be translated, and may be one way for the cell to upregulate stress-response genes that are needed in the UPR.
Although it is clear that ER-stress leads to large scale changes in the protein and RNA content of the ER, it is not yet clear if this leads to immediate structural reorganization in order to accommodate the new needs of the organelle. In addition, it is not yet clear if activation of stress-responsive signaling pathways leads to the modification of intrinsic structural components of the ER.
Interestingly, it has been observed that splicing of XBP1 is activated during meiosis in both Xenopus and budding yeast [ , ], suggesting that changes in ER structure during meiosis could be linked to the ER stress response.
These would both be interesting avenues of future research exploring structural changes in the ER in response to cellular signaling cues. The ER is a complex organelle that plays a pivotal role in protein and lipid synthesis, calcium storage and stress response. Changes in structure in response to cell cycle or developmental state render this organelle highly dynamic.
Several proteins play a role in the proper formation of the different structures of the peripheral ER including the nuclear envelope, sheets and tubules. Regulation exists at multiple steps in the formation and maintenance of these structures, and the ratios of these structures are very different in cells of different functions. In general, cells involved in synthesizing large amounts of protein have higher ratios of sheets, whereas cells involved in lipid synthesis or signaling with other organelles would have higher ratios of tubules.
The generation of these structures relies on a myriad of proteins, involved in either structural aspects of ER morphology by directly affecting the phospholipid bilayer and curvature of membranes or mediating interactions with other organelles or the cytoskeleton.
In addition, proteins with other functions, including nucleases and GTPases, also play a role in network formation.
Recent work has begun to connect our knowledge of the proteins that provide the fundamental shape of the ER to signaling pathways, but much work remains to be done to understand how developmental, cell cycle, and stress pathways change the fundamental shape of the ER in different circumstances.
The strong link of ER-shaping proteins to hereditary human diseases highlights the need for further research into the basic biology of the ER and how this biology changes in response to changes in cellular environment. National Center for Biotechnology Information , U. Cellular and Molecular Life Sciences. Cell Mol Life Sci. Published online Oct 3. Dianne S. Schwarz and Michael D. Michael D. Author information Article notes Copyright and License information Disclaimer. Blower, Email: ude.
Corresponding author. This article has been cited by other articles in PMC. Abstract The endoplasmic reticulum ER is a large, dynamic structure that serves many roles in the cell including calcium storage, protein synthesis and lipid metabolism. Introduction The ER is the largest organelle in the cell and is a major site of protein synthesis and transport, protein folding, lipid and steroid synthesis, carbohydrate metabolism and calcium storage [ 1 — 7 ].
Protein synthesis and folding One of the major functions of the ER is to serve as a site for protein synthesis for secreted and integral membrane proteins [ 8 ], as well as a subpopulation of cytosolic proteins [ 1 ]. Lipid biogenesis While the ER is a major site of protein synthesis, it is also a site of bulk membrane lipid biogenesis [ 4 ], which occurs in the endomembrane compartment that includes the ER and Golgi apparatus.
Regulation of ER shape and function The ER is a complex organelle, involved in protein and lipid synthesis, calcium regulation and interactions with other organelles. Open in a separate window. ER structure There have been several excellent, recent reviews that cover the topic of general ER structure in detail [ 7 , 44 — 48 ], so we will limit our review of the basic ER structure to only those factors that may play a role in changing the shape of ER in response to signaling.
ER shaping proteins ER tubules Peripheral ER structures are just as distinct and diverse as the set of proteins that contribute to their shape. ER sheets We have considered how tubules are formed and maintained, which leads the discussion to sheets, the other peripheral ER structure. ER microtubule interactions It is clear that proteins involved in the promotion, maintenance or stabilization of peripheral ER structures function through interactions with additional proteins or structures, and these interactions are key to proper formation of the ER network.
Changes in ER structure during mitosis During mitosis many cellular structures are dramatically remodeled to facilitate chromosome segregation. Changes in ER during oocyte maturation and fertilization One of the greatest changes during development occurs at fertilization. ER changes in response to ER stress As seen so far, the ER is an organelle of many different functions that must be tightly regulated to carry out the proper functions.
Closing remarks The ER is a complex organelle that plays a pivotal role in protein and lipid synthesis, calcium storage and stress response. References 1. Diversity and selectivity in mRNA translation on the endoplasmic reticulum. Nat Rev Mol Cell Biol. Rapoport TA.
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They're retained and the endoplasmic reticulum becomes engorged because it seems to be constipated, in a way, and the proteins don't get out where they're suppose to go. Then there's the smooth endoplasmic reticulum, which doesn't have those ribosomes on it.
And that smooth endoplasmic reticulum produces other substances needed by the cell. It is found fairly evenly distributed throughout the cytoplasm. Smooth ER is devoted almost exclusively to the manufacture of lipids and in some cases to the metabolism of them and associated products.
In liver cells for example smooth ER enables glycogen that is stored as granules on the external surface of smooth ER to be broken down to glucose. Smooth ER is also involved in the production of steroid hormones in the adrenal cortex and endocrine glands. Smooth ER — the detox stop Smooth ER also plays a large part in detoxifying a number of organic chemicals converting them to safer water-soluble products.
Large amounts of smooth ER are found in liver cells where one of its main functions is to detoxify products of natural metabolism and to endeavour to detoxify overloads of ethanol derived from excess alcoholic drinking and also barbiturates from drug overdose.
To assist with this, smooth ER can double its surface area within a few days, returning to its normal size when the assault has subsided. The contraction of muscle cells is triggered by the orderly release of calcium ions.
These ions are released from the smooth endoplasmic reticulum. Cytoskeleton — the movers and shapers in the cell. Extracellular Matrix and Cell Adhesion Molecules. Endoplasmic reticulum is an organelle found in both eukaryotic animal and plant cells.
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