Quality control in the endoplasmic reticulum protein factory

Sitia, Roberto; Braakman, Ineke

doi:10.1038/nature02262

Cited by 624 publications

(468 citation statements)

References 43 publications

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“…After co-translational insertion into the ER, new proteins undergo folding, assembly, and posttranslational modifications which are scrutinized by a rigorous quality control mechanism (Ellgaard and Helenius, 2003). Misfolded proteins which fail to refold properly are retrotranslocated to the cytosol where they undergo degradation mediated by the ubiquitin-and proteasome system (UPS), a process known as ER-associated degradation (ERAD) (Ahner and Brodsky, 2004;Ellgaard and Helenius, 2003;Kostova and Wolf, 2003;Sitia and Braakman, 2003;Tsai et al, 2002). An increase in protein misfolding within the ER leads to an integrated cellular response, which involves translational attenuation, decreasing the input of new proteins, followed by a transcriptional reaction known as unfolded protein response (UPR) (Hampton, 2003;Harding et al, 2002;Ma and Hendershot, 2002;Shen et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Decreased ER-associated degradation of α-TCR induced by Grp78 depletion with the SubAB cytotoxin

Lass

Kujawa

McConnell

et al. 2008

The International Journal of Biochemistry & Cell Biology

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HeLa cells stably expressing the α chain of T-cell receptor (αTCR), a model substrate of ERAD (ERassociated degradation), were used to analyze the effects of BiP/Grp78 depletion by the SubAB cytotoxin. SubAB induced XBP1 splicing, followed by JNK phosphorylation, eIF2α phosphorylation, upregulation of ATF3/4 and partial ATF6 cleavage. Other markers of ER stress, including elements of ER-associated degradation (ERAD) pathway, as well as markers of cytoplasmic stress, were not induced. SubAB treatment decreased absolute levels of αTCR, which was caused by inhibition of protein synthesis. At the same time, the half-life of αTCR was extended almost fourfold from 70 min to 210 min, suggesting that BiP normally facilitates ERAD. Depletion ofp97/VCP partially rescued SubAB-induced depletion of αTCR, confirming the role of VCP in ERAD of αTCR. It therefore appears that ERAD of αTCR is driven by at least two different ATPase systems located at two sides of the ER membrane, BiP located on the lumenal side, while p97/ VCP on the cytoplasmic side. While SubAB altered cell morphology by inducing cytoplasm vacuolization and accumulation of lipid droplets, caspase activation was partial and subsided after prolonged incubation. Expression of CHOP/GADD153 occurred only after prolonged incubation and was not associated with apoptosis.

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Section: Introductionmentioning

confidence: 99%

Decreased ER-associated degradation of α-TCR induced by Grp78 depletion with the SubAB cytotoxin

Lass

Kujawa

McConnell

et al. 2008

The International Journal of Biochemistry & Cell Biology

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“…There are several events associated with the ER that critically regulate G protein-coupled receptor export. First, similar to many other membrane proteins, receptors must be correctly folded in order to pass the ER quality control mechanism [3,4]. Second, export from the ER and further transport to the cell surface of some G protein-coupled receptors requires specific accessory proteins or chaperones [5][6][7][8].…”

Section: Introductionmentioning

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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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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“…Nature has, therefore, developed a series of strategies to ensure that proteins fold, and remain properly folded, where and when they are required. These strategies include the evolution of specific polypeptide sequences, the involvement of folding catalysts and molecular chaperones, and the development of sophisticated quality control mechanisms [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Probing the origins, diagnosis and treatment of amyloid diseases using antibodies

Dumoulin

Dobson

2004

Biochimie

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The deposition of proteins in the form of amyloid fibrils is the characteristic feature of more than 20 medical conditions affecting the central nervous system or a variety of peripheral tissues. These disorders, which include Alzheimer's disease, the prion diseases and type II diabetes, are of enormous importance in the context of present-day human health and welfare. Extensive research is therefore being carried out to define the molecular details of the mechanism of the pathological conversion of amyloidogenic proteins from their soluble forms into fibrillar structures. This review focuses on recent studies that demonstrate the power of using antibodies or antibody fragments to probe the process of fibril formation, and discusses the emerging potential of these species as diagnostic and therapeutic agents.

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Quality control in the endoplasmic reticulum protein factory

Cited by 624 publications

References 43 publications

Decreased ER-associated degradation of α-TCR induced by Grp78 depletion with the SubAB cytotoxin

Decreased ER-associated degradation of α-TCR induced by Grp78 depletion with the SubAB cytotoxin

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

Probing the origins, diagnosis and treatment of amyloid diseases using antibodies

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