A regulatory link between ER-associated protein degradation and the unfolded-protein response.

Friedlander, Ruth; Jarosch, Ernst; Urban, Jörg; Volkwein, Corinna; Sommer, Thomas

doi:10.1038/35017001

Cited by 433 publications

(350 citation statements)

References 29 publications

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“…This agrees with the finding that treatment of human fibroblasts with SubAB during the early phase of CMV infection downregulates the expression of viral proteins even as late as 96 h after addition of the toxin (Buchkovich et al, 2008). Many reports have indicated that ERAD components are upregulated as part of UPR (Casagrande et al, 2000;Friedlander et al, 2000). However, we have not observed an upregulation of proteins involved in ERAD, such as proteasome subunits, p97/VCP or the channel forming protein derlin 1 even after 16 h of incubation with SubAB.…”

Section: Discusssionsupporting

confidence: 91%

“…ERAD constitutively counteracts ER stress, eliminating misfolded proteins from the ER, however UPR induces its further activation through upregulation of its components (Casagrande et al, 2000;Friedlander et al, 2000). We therefore expected that treatment with SubAB would accelerate ERAD of αTCR.…”

Section: Discusssionmentioning

confidence: 98%

“…Since ER stress is usually associated with increased ER-associated degradation (ERAD) of proteins (Casagrande et al, 2000;Friedlander et al, 2000)., we also looked at different components of the ubiquitin and proteasome system (UPS). The levels of polyubiquitinated proteins were similar in all three cell lines and were not affected by either wild type or mutant SubAB.…”

Section: Subab Induces Er Stress In Different Cell Linesmentioning

confidence: 99%

“…Thus, UPR is an adaptative response allowing the cell to cope with ER stress: However, when UPR is persistent, it leads to apoptosis via transcriptional induction of CHOP/GADD153, TRAF-mediated activation of cJUN N-terminal kinase, and/ or the activation of caspase-12/4 (Boyce and Yuan, 2006;Wu and Kaufman, 2006). ERAD constitutively counteracts ER stress, eliminating misfolded proteins from the ER, but it is further activated as part of UPR (Casagrande et al, 2000;Friedlander et al, 2000). Expression of individual TCR subunits in cell lines which endogenously do not express TCR have served in numerous studies to resolve the molecular determinants for rapid degradation of free TCR subunits (Bonifacino et al, 1989;Bonifacino et al, 1990;Fang et al, 2001;Fayadat and Kopito, 2003;Huppa and Ploegh, 1997;Lenk et al, 2002;Tiwari and Weissman, 2001;Travers et al, 2000;Wileman et al, 1990;Wileman et al, 1993;Yang et al, 1998;Yu et al, 1997;Yu and Kopito, 1999).…”

Section: Introductionmentioning

confidence: 99%

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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: Discusssionsupporting

confidence: 91%

Section: Discusssionmentioning

confidence: 98%

Section: Subab Induces Er Stress In Different Cell Linesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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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“…The ubiquityl ation machinery, consisting of ubiquitin activating enzyme (E1), ubiquitin conjugating enzymes (E2), and ubiquitin ligases (E3), controls substrate targeting via conjugation of ubiquitin, after which proteins are degraded by the proteasome core 41,42 . Unfolded pro teins from the endoplasmic reticulum (ER) are cleared via the ER associated degradation (ERAD) system, which induces trans location of unfolded proteins from the ER to the cytosol, from where they are cleared by the UPS 43,44 .…”

Section: The Proteostasis Network Componentsmentioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

141

126

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The worldwide increase in life expectancy gives rise to an increasing prevalence of cardiac diseases, which remain the leading cause of disability and death in the developed world [1][2][3] . Currently, the mechanisms under lying how ageing contributes to the initiation or acceler ation of cardiac diseases are essentially unresolved. Prevailing theories of ageing centre on gradual derail ment of cellular protein homeostasis -proteostasis -either by design (genetically) or by 'wear and tear' (environmentally) 3 . Central to the role of proteostasis derailment as a major factor in ageing is the observation that protein function declines over time.Proteins are the most versatile and complex macro molecules and are involved in the proper functioning of every biological process 4 . After synthesis as a poly peptide chain from the genetic code, proper function of a protein relies heavily on its correct folding into a 3D native state and on various post translational modifi cations, mostly involving the addition of chem ical groups (including phosphate, acetate, and carbo hydrate). Protein maturation, transport, and ultimately breakdown is monitored and supported by various classes of proteins, collectively called 'protein quality control' (PQC) [3][4][5] . Balanced proteostasis, therefore, depends on proper PQC and is crucial for cellular and organismal health 6 . The intricate network making up the PQC involves numerous proteins, of which the main players are the chaperones and their regula tors 4,7-9 (assisting in folding and refolding of proteins) and the pathways that clear irreversibly misfolded and aggregation prone proteins (the ubiquitin-proteasome system [UPS] and autophagy systems) 9-11 . With ageing, the gradual accumulation of misfolded or damaged pro teins, together with concomitant failure of PQC, results in proteotoxic stress and compromised defence against reactive oxygen species (ROS) 10 , a process that is likely to be accelerated in various age related diseases includ ing neurodegenerative diseases 12,13 , type 2 diabetes mel litus 14 , cancer 15 , and cardiac diseases [16][17][18][19][20] . In addition to the accumulation of misfolded proteins, ageing is accompanied by an imbalance in the proteome, as indi cated by lowered expression of chaperone, proteaso mal, ribosomal, and mitochondrial proteins, whereas proteins related to oxidative stress are upregulated 21,22 . Although mild impairment of proteostasis extends lifespan in Caenorhabditis elegans, referred to as hormesis, sustained impairment is accompanied by loss of PQC to neutralize this effect 3,5 . Importantly, evidence indicates that the amount of soluble, aggregate prone protein oligomers, rather than the abundance of pro tein aggregates, correlates with disease severity 23,24 . Therefore, protein aggregates, which contain both misfolded proteins and elevated levels of chaper ones, constitute an adequate PQC response, aimed at sequestering potentially harmful protein oligomers, rather than embodying the ultimate cellular threat 25 . This ...

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Protein Synthesis and Secretion: Animal Cells

Kaufman

Popolo

2009

Encyclopedia of Industrial Biotechnology

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Many products of interest to the biotechnology industry are synthesized and secreted from specialized cell types. Among the most significant products are those having therapeutic application such as hormones, plasma proteins, and enzymes produced by the endocrine and exocrine glands (for a survey on biopharmaceuticals see Walsh G. Biopharmaceutical products in the US and European markets. 6th ed. BioPlan Associates, Inc.; 2007). The production of many bioproducts takes advantage of recombinant DNA technology to construct vectors designed for high‐level expression and secretion of proteins. Remarkably, a variety of cultured mammalian cells have the capacity to synthesize and secrete a vast array of biologically active proteins that are normally produced only in highly specialized cells. Despite the higher cost of production compared to bacteria, yeast, or insect cells, protein expression in mammalian cells is often obligatory to produce proteins in an enzymatic or biologically active form. However, the particular requirements protein may have often limits the yield and reduces the quality of proteins produced in mammalian cells. To understand factors that affect the quality of proteins, it is necessary to consider what factors affect protein folding, processing, and secretion from mammalian cells. Remarkable progress has been made during the past two decades in understanding the molecular basis of protein secretion. This article briefly describes how proteins are synthesized, processed, and transported through the secretory pathway to the cell surface. Particular emphasis is focused on the early secretory pathway because this is frequently the rate‐limiting step. Biotechnology can take advantage of our expanding knowledge of the secretory pathway to design new strategies to improve and optimize the secretion of high‐quality recombinant proteins from mammalian cells.

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A regulatory link between ER-associated protein degradation and the unfolded-protein response.

Cited by 433 publications

References 29 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

Proteostasis in cardiac health and disease

Protein Synthesis and Secretion: Animal Cells

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