Traffic Jams II: An Update of Diseases of Intracellular Transport

Aridor, Meir; Hannan, Lisa A.

doi:10.1034/j.1600-0854.2002.31103.x

Cited by 193 publications

(121 citation statements)

References 64 publications

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“…The diseases may result from defective transport of the receptors out of the ER (resulting in receptor retention in the ER) and/or a defect in the machinery which transports receptors to their functional destination after ER exit. For example, numerous naturally occurring mutations in G protein-coupled receptors leading to ER retention have been implicated in inherited diseases such as retinitis pigmentosa, nephrogenic diabetes insipidus and male pseudohermaphroditism [42][43][44]. We have demonstrated that different G protein-coupled receptors may use distinct pathways to move from the ER to the cell surface [23] and that selective G protein-coupled receptors may carry a specific code for exit from the ER [22].…”

Section: Discussionmentioning

confidence: 88%

“…Defective transport of the receptors from the ER to the cell surface is associated with the pathogenesis of a variety of human diseases [42,43]. The diseases may result from defective transport of the receptors out of the ER (resulting in receptor retention in the ER) and/or a defect in the machinery which transports receptors to their functional destination after ER exit.…”

Section: Discussionmentioning

confidence: 99%

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Cell-surface targeting of α2-adrenergic receptors — Inhibition by a transport deficient mutant through dimerization

Zhou

Filipeanu

Duvernay

et al. 2006

Cellular Signalling

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We previously demonstrated that the α 2B -adrenergic receptor mutant, in which the F(x) 6 IL motif in the membrane-proximal carboxyl terminus were mutated to alanines (α 2B -ARm), is deficient in export from the endoplasmic reticulum (ER). In this report, we determined if α 2B -ARm could modulate transport from the ER to the cell surface and signaling of its wild-type counterpart. Transient expression of α 2B -ARm in HEK293T cells markedly inhibited cell-surface expression of wild-type α 2B -AR, as measured by radioligand binding. Subcellular localization demonstrated that α 2B -ARm trapped α 2B -AR in the ER. The α 2B -AR was shown to form homodimers and heterodimers with α 2B -ARm as measured by co-immunoprecipitation of the receptors tagged with green fluorescent protein and hemagglutinin epitopes. In addition to α 2B -AR, the transport of α 2A -AR and α 2C -AR to the cell surface was also inhibited by α 2B -ARm. Furthermore, transient expression of α 2B -ARm significantly reduced cell-surface expression of endogenous α 2 -AR in NG108-15 and HT29 cells. Consistent with its effect on α 2 -AR cell-surface expression, α 2B -ARm attenuated α 2A -AR-and α 2B -AR-mediated ERK1/2 activation. These data demonstrated that the ER-retained mutant α 2B -ARm conferred a dominant negative effect on the cell-surface expression of wild-type α 2 -AR, which is likely mediated through heterodimerization. These data indicate a crucial role of ER export in the regulation of cell-surface targeting and signaling of G protein-coupled receptors.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Cell-surface targeting of α2-adrenergic receptors — Inhibition by a transport deficient mutant through dimerization

Zhou

Filipeanu

Duvernay

et al. 2006

Cellular Signalling

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“…[5][6][7] Quality control of protein folding is of importance in congenital diseases caused by point mutations that result in the synthesis of misfolded glycoproteins. 8 Mutations in the water channel aquaporin-2 (AQP2) can cause nephrogenic diabetes insipidus (NDI), in which patients are unable to concentrate urine in response to the anti-diuretic hormone arginine-vasopressin. 9 -11 If not corrected, this defect results in a deregulated whole-body water homeostasis that is accompanied by various symptoms of dehydration.…”

Section: Mutations In the Water Channel Aquaporin-2 (Aqp2) Can Cause mentioning

confidence: 99%

The Proteasome Is Involved in the Degradation of Different Aquaporin-2 Mutants Causing Nephrogenic Diabetes Insipidus

Hirano

Zuber

Roth

et al. 2003

The American Journal of Pathology

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Mutations in the water channel aquaporin-2 (AQP2) can cause congenital nephrogenic diabetes insipidus. To reveal the possible involvement of the protein quality control system in processing AQP2 mutants, we created an in vitro system of clone 9 hepatocytes stably expressing endoplasmic reticulum-retained T126M AQP2 and misrouted E258K AQP2 as well as wild-type AQP2 and studied their biosynthesis, degradation, and intracellular distribution. Mutant and wild-type AQP2 were synthesized as 29-kd nonglycosylated and 32-kd core-glycosylated forms in the endoplasmic reticulum. The wild-type AQP2 had a t 1/2 of 4.6 hours. Remarkable differences in the degradation kinetics were observed for the glycosylated and nonglycosylated T126M AQP2 (t 1/2 ‫؍‬ 2.0 hours versus 0.9 hours). Moreover, their degradation was depending on proteasomal activity as demonstrated in inhibition studies. Degradation of E258K AQP2 also occurred rapidly (t 1/2 ‫؍‬ 1.8 hours) but in a proteasome-and lysosome-dependent manner. By triple confocal immunofluorescence microscopy misrouting of E258K to lysosomes via the Golgi apparatus could be demonstrated. Notwithstanding the differences in degradation kinetics and subcellular distribution such as endoplasmic reticulum-retention and misrouting to lysosomes, both T126M and E258K AQP2 were efficiently degraded. This implies the involvement of different protein quality control processes in the processing of these AQP2 mutants. The endoplasmic reticulum (ER) represents a site of quality control of glycoprotein folding. 1,2 Misfolded glycoproteins are recognized and retained by the concerted action of chaperones, lectins, and modifying enzymes such as UDP-glucose:glycoprotein glucosyltransferase and glucosidase II. 3 Glycoproteins failing to achieve their correct conformation might become retrotranslocated to the cytosol 4 and degraded by the ubiquitin-proteasome pathway, a process referred to as ER-associated protein degradation. [5][6][7] Quality control of protein folding is of importance in congenital diseases caused by point mutations that result in the synthesis of misfolded glycoproteins. 8 Mutations in the water channel aquaporin-2 (AQP2) can cause nephrogenic diabetes insipidus (NDI), in which patients are unable to concentrate urine in response to the anti-diuretic hormone arginine-vasopressin. 9 -11 If not corrected, this defect results in a deregulated whole-body water homeostasis that is accompanied by various symptoms of dehydration. 12 AQP2 belongs to the large family of AQPs, 13,14 and is a 29-kd polytope membrane protein that contains a single N-glycosylation site and two phosphorylation sites, and is present in the principal cells of renal collecting ducts. 15,16 In states of hypernatremia or hypovolemia, translocation of phosphorylated AQP2 homotetramers from vesicles to the apical plasma membrane of the principal cells is triggered by a signal transduction cascade induced by arginine-vasopressin. 16 -18 Alike to normal human kidney, 19 wild-type (wt) AQP2, when expressed in Xenopus ooc...

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“…[11][12][13][14] ER stress and the apoptotic program coupled to it have been implicated in many important pathologies, including diabetes, obesity, neurodegenerative disorders, viral infection, and a variety of ER storage diseases. 5,[15][16][17][18][19] Nevertheless, the initiation and execution steps of ER stress-induced apoptosis in mammals remain poorly understood. Classical genetics has allowed detailed dissection of the ESR in lower organisms such as Saccharomyces cerevisiae, but greater complexity and intractable genetics have hindered progress in mammalian systems.…”

mentioning

confidence: 99%

A pharmacoproteomic approach implicates eukaryotic elongation factor 2 kinase in ER stress-induced cell death

Boyce

Ryazanov

et al. 2008

Cell Death Differ

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Apoptosis triggered by endoplasmic reticulum (ER) stress has been implicated in many diseases but its cellular regulation remains poorly understood. Previously, we identified salubrinal (sal), a small molecule that protects cells from ER stressinduced apoptosis by selectively activating a subset of endogenous ER stress-signaling events. Here, we use sal as a probe in a proteomic approach to discover new information about the endogenous cellular response to ER stress. We show that sal induces phosphorylation of the translation elongation factor eukaryotic translation elongation factor 2 (eEF-2), an event that depends on eEF-2 kinase (eEF-2K). ER stress itself also induces eEF-2K-dependent eEF-2 phosphorylation, and this pathway promotes translational arrest and cell death in this context, identifying eEF-2K as a hitherto unknown regulator of ER stress-induced apoptosis. Finally, we use both sal and ER stress models to show that eEF-2 phosphorylation can be activated by at least two signaling mechanisms. Our work identifies eEF-2K as a new component of the ER stress response and underlines the utility of novel small molecules in discovering new cell biology. Cell Death and Differentiation (2008) 15, 589-599; doi:10.1038/sj.cdd.4402296; published online 11 January 2008 The endoplasmic reticulum (ER) serves as the primary processing site for membrane and secreted proteins. The ER recruits translating ribosomes, translocates newly synthesized polypeptides into its lumen, and promotes a variety of post-translational modifications and chaperone-facilitated protein folding. 1,2 Proper ER function is critical for numerous aspects of cell physiology, including vesicle trafficking, lipid and membrane biogenesis, and protein targeting and secretion. Accordingly, cells react rapidly to various forms of ER dysfunction -including the accumulation of unfolded, misfolded or excessive protein, ER lipid or glycolipid imbalances, or changes in the redox or ionic conditions of the ER lumenthrough a set of adaptive pathways known collectively as the ER stress response (ESR). [2][3][4][5] The ESR promotes cell survival both by increasing the capacity of the ER to fold and process client proteins and by reducing the amount of protein inside the ER. These effects are achieved through three major pathways: (1) the unfolded protein response, a transcription-dependent induction of ER lumenal chaperone proteins and many other components of the secretory apparatus, which augments the polypeptide processing capacity of the ER; 5,6 (2) the activation of proteasome-dependent ER-associated degradation to remove proteins from the ER; 7,8 and (3) the control of protein translation to modulate the polypeptide traffic into the ER. 9,10 Normally, this suite of responses succeeds in restoring ER homeostasis. However, in metazoans, persistent or intense ER stress can also trigger apoptosis. [11][12][13][14] ER stress and the apoptotic program coupled to it have been implicated in many important pathologies, including diabetes, obesity, neurodegenerativ...

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Traffic Jams II: An Update of Diseases of Intracellular Transport

Cited by 193 publications

References 64 publications

Cell-surface targeting of α2-adrenergic receptors — Inhibition by a transport deficient mutant through dimerization

Cell-surface targeting of α2-adrenergic receptors — Inhibition by a transport deficient mutant through dimerization

The Proteasome Is Involved in the Degradation of Different Aquaporin-2 Mutants Causing Nephrogenic Diabetes Insipidus

A pharmacoproteomic approach implicates eukaryotic elongation factor 2 kinase in ER stress-induced cell death

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