The dynamic ER: experimental approaches and current questions

Federovitch, Christine M.; Ron, David; Hampton, Randolph Y.

doi:10.1016/j.ceb.2005.06.010

Cited by 100 publications

(68 citation statements)

References 33 publications

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“…Overexpression of single ER membrane proteins, whether induced by drugs or by transfection, often causes proliferation of ER membranes [60]. Thus, in these studies, ER proliferation correlated with ER restructuring and the question of whether ER restructuring can occur independently of proliferation was not addressed.…”

Section: Smooth Ermentioning

confidence: 97%

Endoplasmic reticulum architecture: structures in flux

Borgese

Francolini

Snapp

2006

Current Opinion in Cell Biology

206

147

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The endoplasmic reticulum (ER) is a dynamic pleiomorphic organelle containing continuous but distinct subdomains. The diversity of ER structures parallels its many functions, including secretory protein biogenesis, lipid synthesis, drug metabolism and Ca 2+ signaling. Recent studies are revealing how elaborate ER structures arise in response to subtle changes in protein levels, dynamics, and interactions as well as in response to alterations in cytosolic ion concentrations. Subdomain formation appears to be governed by principles of self-organization. Once formed, ER subdomains remain malleable and can be rapidly transformed into alternative structures in response to altered conditions. The mechanisms that modulate ER structure are likely to be important for the generation of the characteristic shapes of other organelles.

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Section: Smooth Ermentioning

confidence: 97%

Endoplasmic reticulum architecture: structures in flux

Borgese

Francolini

Snapp

2006

Current Opinion in Cell Biology

206

147

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“…As differentiation of these tissues progresses, their cells take on a morphology that is dominated by membranous elements of the secretory pathway, most notably rough endoplasmic reticulum (ER) (Jamieson and Palade, 1967a,b). A similar situation exists in the immune system, in which B-lymphocytes differentiate into plasma cells as the result of being triggered by the appropriate antigen Shohat et al, 1973;Wiest et al, 1989Wiest et al, , 1990Chen-Kiang 1995;Gass et al, 2002;Iwakoshi et al, 2003;Federovitch et al, 2005;Fagone et al, 2007). A prerequisite for achieving such a "secretory phenotype" is intracellular membrane proliferation, which is in turn needed to expand the cell's capacity to synthesize, process, transport, and ultimately release peptides and proteins into the extracellular space.…”

mentioning

confidence: 99%

Knockdown of p180 Eliminates the Terminal Differentiation of a Secretory Cell Line

Benyamini

Webster

Meyer

2009

MBoC

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We have previously reported that the expression in yeast of an integral membrane protein (p180) of the endoplasmic reticulum (ER), isolated for its ability to mediate ribosome binding, is capable of inducing new membrane biogenesis and an increase in secretory capacity. To demonstrate that p180 is necessary and sufficient for terminal differentiation and acquisition of a secretory phenotype in mammalian cells, we studied the differentiation of a secretory cell line where p180 levels had been significantly reduced using RNAi technology and by transiently expressing p180 in nonsecretory cells. A human monocytic (THP-1) cell line, that can acquire macrophage-like properties, failed to proliferate rough ER when p180 levels were lowered. The Golgi compartment and the secretion of apolipoprotein E (Apo E) were dramatically affected in cells expressing reduced p180 levels. On the other hand, expression of p180 in a human embryonic kidney nonsecretory cell line (HEK293) showed a significant increase in proliferation of rough ER membranes and Golgi complexes. The results obtained from knockdown and overexpression experiments demonstrate that p180 is both necessary and sufficient to induce a secretory phenotype in mammalian cells. These findings support a central role for p180 in the terminal differentiation of secretory cells and tissues. INTRODUCTIONAt the morphological level, the development of secretory cells and tissues has been well documented. From a molecular point of view, details of how cells acquire the ability to secrete at high levels as part of the process of their terminal differentiation are less well understood. Early in mammalian embryogenesis, the cytoplasm of cells of exocrine tissues, such as pancreas or liver, possesses a mere fraction of the intracellular organelles that they ultimately acquire upon terminal differentiation (Dallner et al., 1966a,b;Pictet et al., 1972;Slack, 1995;Debas, 1997). As differentiation of these tissues progresses, their cells take on a morphology that is dominated by membranous elements of the secretory pathway, most notably rough endoplasmic reticulum (ER) (Jamieson and Palade, 1967a,b). A similar situation exists in the immune system, in which B-lymphocytes differentiate into plasma cells as the result of being triggered by the appropriate antigen Shohat et al., 1973;Wiest et al., 1989Wiest et al., , 1990Chen-Kiang 1995;Gass et al., 2002;Iwakoshi et al., 2003;Federovitch et al., 2005;Fagone et al., 2007). A prerequisite for achieving such a "secretory phenotype" is intracellular membrane proliferation, which is in turn needed to expand the cell's capacity to synthesize, process, transport, and ultimately release peptides and proteins into the extracellular space.Limited success has been achieved, in a few cell types, in recapitulating membrane proliferation reminiscent of secretory cell differentiation. Through the ectopic expression of membrane proteins, ER-like membranes have been produced in yeast as well as in various mammalian cells (Wright et al., 1988;Vergeres et ...

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“…ER abundance, therefore, is regulated according to the demands on the secretory pathway. However, the mechanisms that regulate ER biogenesis are incompletely defined (7).…”

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confidence: 99%

Coordinate Regulation of Phospholipid Biosynthesis and Secretory Pathway Gene Expression in XBP-1(S)-induced Endoplasmic Reticulum Biogenesis

Sriburi

Bommiasamy

Buldak

et al. 2007

Journal of Biological Chemistry

228

200

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Development of the expansive endoplasmic reticulum (ER) present in specialized secretory cell types requires X-box-binding protein-1 (Xbp-1). Enforced expression of XBP-1(S), a transcriptional activator generated by unfolded protein responsemediated splicing of Xbp-1 mRNA, is sufficient to induce proliferation of rough ER. We previously showed that XBP-1(S)-induced ER biogenesis in fibroblasts correlates with increased production of phosphatidylcholine (PtdCho), the primary phospholipid of the ER membrane, and enhanced activities of the choline cytidylyltransferase (CCT) and cholinephosphotransferase enzymes in the cytidine diphosphocholine (CDP-choline) pathway of PtdCho biosynthesis. Here, we report that the level and synthesis of CCT, the rate-limiting enzyme in the CDPcholine pathway, is elevated in fibroblasts overexpressing XBP-1(S). Furthermore, overexpression experiments demonstrated that raising the activity of CCT, but not cholinephosphotransferase, is sufficient to augment PtdCho biosynthesis in fibroblasts, indicating that XBP-1(S) increases the output of the CDP-choline pathway primarily via its effects on CCT. Finally, fibroblasts overexpressing CCT up-regulated PtdCho synthesis to a level similar to that in XBP-1(S)-transduced cells but exhibited only a small increase in rough ER and no induction of secretory pathway genes. The more robust XBP-1(S)-induced ER expansion was accompanied by induction of a wide array of genes encoding proteins that function either in the ER or at other steps in the secretory pathway. We propose that XBP-1(S) regulates ER abundance by coordinately increasing the supply of membrane phospholipids and ER proteins, the key ingredients for ER biogenesis. The endoplasmic reticulum (ER)3 is a multifunctional organelle responsible for the folding and assembly of all proteins targeted to the secretory pathway (1). As such, the ER can adapt to accommodate an increased load of nascent polypeptides. For example, when B-lymphocytes differentiate into antibody-secreting plasma cells, an elaborate network of rough ER develops to facilitate immunoglobulin production (2-4). Likewise, the rough ER is highly developed in other specialized secretory cell types such as pancreatic acinar cells that secrete copious amounts of digestive enzymes (5). In contrast, the ER is sparse in non-secretory cells, such as reticulocytes (6). ER abundance, therefore, is regulated according to the demands on the secretory pathway. However, the mechanisms that regulate ER biogenesis are incompletely defined (7).A key regulator of ER homeostasis is the unfolded protein response (UPR) pathway, a complex signaling system emanating from the ER membrane (8). When the protein folding capacity of the ER is challenged, the UPR relieves the resulting stress by repressing translation, increasing expression of ER chaperones and folding enzymes, and enhancing ER-associated degradation (8). In addition, recent studies have uncovered a connection between the UPR and ER abundance (9, 10). The UPR-regulated transcription fa...

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The dynamic ER: experimental approaches and current questions

Cited by 100 publications

References 33 publications

Endoplasmic reticulum architecture: structures in flux

Endoplasmic reticulum architecture: structures in flux

Knockdown of p180 Eliminates the Terminal Differentiation of a Secretory Cell Line

Coordinate Regulation of Phospholipid Biosynthesis and Secretory Pathway Gene Expression in XBP-1(S)-induced Endoplasmic Reticulum Biogenesis

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