ER stress and the unfolded protein response

Schröder, Martin; Kaufman, Randal J.

doi:10.1016/j.mrfmmm.2004.06.056

Cited by 1,575 publications

(1,411 citation statements)

References 314 publications

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“…hence the early phases of UPR are induced in cells treated with extracellular mutant SOD1 G93a . We then examined cells for the later, pro-apoptotic phase of UPR using immunocytochemistry for nuclear ChOP [30,31]. after 72 h treatment, a significant increase in nuclear ChOP immunoreactivity was observed in NSC-34 cells treated with SOD1 G93a compared to untreated and SOD1 Wt treated cells ( Fig.…”

Section: Uptake Of Extracellular Sod1 Wt and Sod1 G93a By Neuronal Cellsmentioning

confidence: 99%

Extracellular wildtype and mutant SOD1 induces ER–Golgi pathology characteristic of amyotrophic lateral sclerosis in neuronal cells

Sundaramoorthy

Walker

Yerbury

et al. 2013

Cell. Mol. Life Sci.

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Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing neurodegenerative disorder and the majority of ALS is sporadic, where misfolding and aggregation of Cu/Zn-superoxide dismutase (SOD1) is a feature shared with familial mutant-SOD1 cases. ALS is characterized by progressive neurospatial spread of pathology among motor neurons, and recently the transfer of extracellular, aggregated mutant SOD1 between cells was demonstrated in culture. However, there is currently no evidence that uptake of SOD1 into cells initiates neurodegenerative pathways reminiscent of ALS pathology. Similarly, whilst dysfunction to the ERGolgi compartments is increasingly implicated in the pathogenesis of both sporadic and familial ALS, it remains unclear whether misfolded, wildtype SOD1 triggers ER-Golgi dysfunction. In this study we show that both extracellular, native wildtype and mutant SOD1 are taken up by macropinocytosis into neuronal cells. Hence uptake does not depend on SOD1 mutation or misfolding. We also demonstrate that purified mutant SOD1 added exogenously to neuronal cells inhibits protein transport between the ER-Golgi apparatus, leading to Golgi fragmentation, induction of ER stress and apoptotic cell death. Furthermore, we show that extracellular, aggregated, wildtype SOD1 also induces ER-Golgi pathology similar to mutant SOD1, leading to apoptotic cell death. Hence extracellular misfolded wildtype or mutant SOD1 induce dysfunction to ERGolgi compartments characteristic of ALS in neuronal cells, implicating extracellular SOD1 in the spread of pathology among motor neurons in both sporadic and familial ALS. Abstract amyotrophic lateral sclerosis (aLS) is a fatal and rapidly progressing neurodegenerative disorder and the majority of aLS is sporadic, where misfolding and aggregation of Cu/Zn-superoxide dismutase (SOD1) is a feature shared with familial mutant-SOD1 cases. aLS is characterized by progressive neurospatial spread of pathology among motor neurons, and recently the transfer of extracellular, aggregated mutant SOD1 between cells was demonstrated in culture. however, there is currently no evidence that uptake of SOD1 into cells initiates neurodegenerative pathways reminiscent of aLS pathology. Similarly, whilst dysfunction to the eR-Golgi compartments is increasingly implicated in the pathogenesis of both sporadic and familial aLS, it remains unclear whether misfolded, wildtype SOD1 triggers eR-Golgi dysfunction. In this study we show that both extracellular, native wildtype and mutant SOD1 are taken up by macropinocytosis into neuronal cells. hence uptake does not depend on SOD1 mutation or misfolding. We also demonstrate that purified mutant SOD1 added exogenously to neuronal cells inhibits protein transport between the eR-Golgi apparatus, leading to Golgi fragmentation, induction of eR stress and apoptotic cell death. Furthermore, we show that extracellular, aggregated, wildtype SOD1 also induces eR-Golgi pathology similar to mutant SOD1, leading to apoptotic cell death. hence extracellu...

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Section: Uptake Of Extracellular Sod1 Wt and Sod1 G93a By Neuronal Cellsmentioning

confidence: 99%

Extracellular wildtype and mutant SOD1 induces ER–Golgi pathology characteristic of amyotrophic lateral sclerosis in neuronal cells

Sundaramoorthy

Walker

Yerbury

et al. 2013

Cell. Mol. Life Sci.

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“…The mechanisms causing the loss of beta cell function and mass in type 2 diabetes are still debated [8][9][10]. It has been recently proposed that alterations of endoplasmic reticulum (ER) function in the beta cell contribute to cell dysfunction and death [10][11][12][13][14][15][16]. The ER is central to several important cellular functions, including post-translational modifications, folding and assembly of newly synthesised secretory proteins, and calcium storage [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

“…It has been recently proposed that alterations of endoplasmic reticulum (ER) function in the beta cell contribute to cell dysfunction and death [10][11][12][13][14][15][16]. The ER is central to several important cellular functions, including post-translational modifications, folding and assembly of newly synthesised secretory proteins, and calcium storage [14][15][16]. Because beta cells need to synthesise and secrete large quantities of insulin they have a well developed ER and a remarkable production of proteins involved in ER function [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

“…The ER is central to several important cellular functions, including post-translational modifications, folding and assembly of newly synthesised secretory proteins, and calcium storage [14][15][16]. Because beta cells need to synthesise and secrete large quantities of insulin they have a well developed ER and a remarkable production of proteins involved in ER function [14][15][16]. When ER function is impaired, due for example to accumulation of mutant folding-incompetent proteins, calcium depletion, over-production of proteins, or viral infection, ER stress develops [10,11,14,15].…”

Section: Introductionmentioning

confidence: 99%

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The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients

et al. 2007

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Aims/hypothesis Pancreatic beta cells have highly developed endoplasmic reticulum (ER) due to their role in insulin secretion. Since ER stress has been associated with beta cell dysfunction, we studied several features of beta cell ER in human type 2 diabetes. Methods Pancreatic samples and/or isolated islets from non-diabetic controls (ND) and type 2 diabetes patients were evaluated for insulin secretion, apoptosis (electron microscopy and ELISA), morphometric ER assessment (electron microscopy), and expression of ER stress markers in beta cell prepared by laser capture microdissection and in isolated islets.Results Insulin release was lower and beta cell apoptosis higher in type 2 diabetes than ND islets. ER density volume was significantly increased in type 2 diabetes beta cells. Expression of alpha-mannosidase (also known as mannosidase, alpha, class 1A, member 1) and UDP-glucose glycoprotein glucosyl transferase like 2 (UGCGL2), assessed by microarray and/or real-time reverse transcriptase polymerase chain reaction (RT-PCR), differed between ND and type 2 diabetes beta cells. Expression of immunoglobulin heavy chain binding protein (BiP, also known as heat shock 70 kDa protein 5 [glucose-regulated protein, 78 kDa] [HSPA5]), X-box binding protein 1 (XBP-1, also known as XBP1) and C/EBP homologous protein (CHOP, also known as damage-inducible transcript 3 [DDIT3]) was not higher in type 2 diabetes beta cell or isolated islets cultured at 5.5 mmol/l glucose (microarray and real-time RT-PCR) than in ND samples. When islets were cultured for 24 h at 11

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“…Both compounds induce stress to the endoplasmic reticulum (ER) and trigger the unfolded protein response (UPR) (Schroder and Kaufman, 2005). Thapsigargin affects calcium flux between ER and the cytoplasm, whereas the latter targets protein glycosylation (Kim et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

p53 isoforms gain functions

Olivares‐Illana

Fåhræus

2010

Oncogene

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Many different cell stress pathways converge on p53 to induce a number of distinct cell biological responses such as G1 or G2 arrest, senescence or apoptosis. One of the outstanding questions with regard to p53 is how the cells can differentiate between different stresses so that p53 activation leads to the correct response. It has been known for some time that the p53 gene expresses isoforms that carry unique domains and properties, and more recent works have started to reveal some of their functions. The alternative mRNA translation product p53/47, which lacks the first 40 codons, including the first of p53's two trans-activation domains, is being linked to endoplasmic reticulum stress and the unfolded protein response to which it causes a specific G2 arrest. On the other hand, p53 itself induces G1 arrest and has no effect on the G2. The two isoforms D133p53, which lacks the first 133 amino acids, and p53b, which carries an alternative C-terminus, are derived from alternative promoter usage or splicing, respectively, and are together implied in controlling cellular senescence. Hence, through different mechanisms of gene expression control, alternative levels of p53 isoforms help the cell to differentiate between p53 activation and the response to diverse stresses. This holds promise to a better understanding of how upstream and downstream p53 pathways have evolved relative to specific p53 domains.

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ER stress and the unfolded protein response

Cited by 1,575 publications

References 314 publications

Extracellular wildtype and mutant SOD1 induces ER–Golgi pathology characteristic of amyotrophic lateral sclerosis in neuronal cells

Extracellular wildtype and mutant SOD1 induces ER–Golgi pathology characteristic of amyotrophic lateral sclerosis in neuronal cells

The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients

p53 isoforms gain functions

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