Imaging of single cell responses to ER stress indicates that the relative dynamics of IRE1/XBP1 and PERK/ATF4 signalling rather than a switch between signalling branches determine cell survival

Walter, Franziska; Schmid, Jasmin; Düßmann, Heiko; Concannon, Caoimhín G.; Prehn, Jochen H.M.

doi:10.1038/cdd.2014.241

Cited by 113 publications

(102 citation statements)

References 33 publications

(42 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The FOS HPLCprofiles could not reveal total suppression of protein synthesis by switches between these branches and PERK as the glycan Man 4 GlcNAc 1 was present in all spectra indicating a continued support of the dolichol phosphate cycle. Our findings are agreed with the idea that progression of a disease depends on dynamics of UPR branches rather than a switch between them [26].…”

Section: Fig 4 Glycomarkers Of Er Stress and Lysosomal-endosomal Sysupporting

confidence: 81%

Serum glycomarkers of endoplasmic reticulum and lysosomal-endosomal system stress in human healthy aging and diseases

Pismenetskaya¹,

Butters²

2017

Ukr.Biochem.J.

View full text Add to dashboard Cite

To verify the idea that extracellular free oligosaccharides might be able to reflect the functional status of the endoplasmic reticulum (ER) and lysosomal-endosomal system, HPLC-profiles of serum-derived free oligosaccharides (FOS) in human healthyT he multilayered protein quality assurance system encompasses almost all cellular organelles, a network of biochemical processes and a multiplex of intracellular and extracellular signaling cascades [1][2][3][4][5]. At the centre of this wide cellular landscape there are two main hubs -the endoplasmic reticulum (ER) and lysosomal-endosomal system. The former is responsible for quality-reliable guarantee of newly synthesized proteins, the latterfor effective degradation of mature proteins, incorrectly folded proteins and their adducts.The endoplasmic reticulum provides an interconnected space for translation, co-translational and post-translational modifications, folding and assembling of secreted, organelle-targeted and membrane proteins. Only properly folded and assembled proteins can be transported out of the ER via the Golgi apparatus and cytosol to the endpoint of their functional actions -cellular organelles, plasma membrane and extracellular space. Native protein conformation is achieved due to unique environment of the ER lumen and a specific co-translational modification of proteins -N-glycosylation. The oxidation/ reductive conditions of the ER lumen ensure the formation of disulfide bonds maintaining the tertiary and quaternary structure of proteins. The high level of functional chaperone proteins in the ER facilitates protein folding. The high Ca 2+ concentration in the lumen is essential for Ca 2+ -dependent chaperonesprotein interactions. Any disturbance of these three determinants can lead to protein unfolding or misfolding [6].Cells monitor protein folding by a protein quali ty control (QC) system is inbuilt in the ER and

show abstract

Section: Fig 4 Glycomarkers Of Er Stress and Lysosomal-endosomal Sysupporting

confidence: 81%

Serum glycomarkers of endoplasmic reticulum and lysosomal-endosomal system stress in human healthy aging and diseases

Pismenetskaya¹,

Butters²

2017

Ukr.Biochem.J.

View full text Add to dashboard Cite

show abstract

“…XBP1s deficiency or premature attenuation of IRE1/XBP1s signaling during ER stress promotes sustained activation of PERK/CHOP and cell death. 6,12,18 Moreover, sustained IRE1/XBP1 activity enhance cell survival in conditions of severe stress, 11 further supporting a protective role for this pathway. We reported that pancreatic acinar cells express XBP1s in physiological conditions, and that Xbp1 genetic deletion in mice impairs digestive enzyme secretory responses in acinar cells, and decreases the number of zymogen granules in pancreas of ethanol-fed mice.…”

Section: Resultsmentioning

confidence: 90%

“…10 Early induction of XBP1s upon ER stress is critical for ER adaptation to stress and cell survival, while premature termination of this signal leads to ER dysfunction and cell death. 11, 12 …”

Section: Introductionmentioning

confidence: 99%

The Combination of Alcohol and Cigarette Smoke Induces Endoplasmic Reticulum Stress and Cell Death in Pancreatic Acinar Cells

Lugea

Gerloff

et al. 2017

Gastroenterology

View full text Add to dashboard Cite

Background & Aims Smoking, an independent risk factor for pancreatitis, accelerates the development of alcoholic pancreatitis. Alcohol feeding of mice induces upregulation of spliced X-box binding protein 1 (XBP1s), which regulates the endoplasmic reticulum (ER) unfolded protein response and promotes cell survival upon ER stress. We examined whether smoking affects the adaptive mechanisms induced by alcohol and accelerates disorders of the ER in pancreatic acinar cells. Methods We studied the combined effects of ethanol and cigarette smoke extract (CSE) on ER-stress and cell death responses in mouse and human primary acini and the acinar cell line AR42J. Cells were incubated with ethanol (EtOH, 50 mM), CSE (20–40 μg/ml), or both (CSE+EtOH), and analyzed by immunoblotting, quantitative reverse transcription PCR, and cell death assays. Some cells were incubated with MKC-3946, an inhibitor of endoplasmic reticulum to nucleus signaling 1 (ERN1, also called IRE1) that blocks XBP1s formation. Male Sprague-Dawley rats were fed isocaloric amounts of an ethanol-containing (Lieber-DeCarli) or control diet for 11 weeks and exposed to cigarette smoke or room air in an exposure chamber for 2 hours each day. During the last 3 weeks, a subset of rats received intravenous injections of lipopolysaccharide (LPS, 3 mg/kg per weeks) to induce pancreatitis or saline (control). Pancreatic tissues were collected and analyzed by histology and immunostaining techniques. Results In AR42J and primary acini, CSE+EtOH induced cell death (necrosis and apoptosis), but neither agent alone had this effect. Cell death was associated with a significant decrease in expression of XBP1s. CSE+EtOH, but neither agent alone, slightly decreased ATP levels in AR42J cells, but induced oxidative stress and sustained activation (phosphorylation) of eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3, also called PERK) and increased protein levels of DNA damage inducible transcript 3 (DDIT3, also called CHOP). CHOP regulates transcription to promote apoptosis. Incubation of AR42J or primary mouse or human acinar cells with MKC-3946 reduced expression of XBP1s, increased levels of CHOP and induced cell death. In rats fed ethanol diet, exposure to cigarette smoke increased ER stress in acinar cells and sensitized the pancreas to LPS-induced pathology. Conclusions Cigarette smoke promotes cell death and features of pancreatitis in ethanol-sensitized acinar cells by suppressing the adaptive unfolded protein response signaling pathway. It also activates ER stress pathways that promote acinar cell death.

show abstract

“…Unlike the protective role of IRE1α pathway in the early stages of infection, the PERK pathway plays an apoptotic role in the late stages. Similarly, an early onset of XBP-1 splicing and a slow translation of ATF4 for cell survival were observed by imaging the single cell response to ER stress (Walter et al, 2015). We also confirmed this apoptosis caused by ER stress is beneficial in controlling the number of intracellular bacteria by pre-treatment with the specific agonist and inhibitor of ER stress.…”

Section: Discussionmentioning

confidence: 91%

Mycobacterium bovis Induces Endoplasmic Reticulum Stress Mediated-Apoptosis by Activating IRF3 in a Murine Macrophage Cell Line

Cui

Zhao

Sreevatsan

et al. 2016

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

Mycobacterium bovis (M. bovis) is highly adapted to macrophages and has developed multiple mechanisms to resist intracellular assaults. However, the host cells in turn deploy a multipronged defense mechanism to control bacterial infection. Endoplasmic reticulum (ER) stress-mediated apoptosis is one such primary defense mechanism. However, the role of interferon regulatory factor 3 (IRF3) between ER stress and apoptosis during M. bovis infection is unknown. Here, we demonstrate that M. bovis effectively induced apoptosis in murine macrophages. Caspase-12, caspase-9, and caspase-3 were activated over a 48 h infection period. The splicing of XBP-1 mRNA and the level of phosphorylation of eIF2α, indicators of ER stress, significantly increased at early time points after M. bovis infection. The expansion of the ER compartment, a morphological hallmark of ER stress, was observed at 6 h. Pre-treatment of Raw 264.7 cells with 4-PBA (an ER stress-inhibitor) reduced the activation of the ER stress indicators, caspase activation and its downstream poly (ADP-ribose) polymerase (PARP) cleavage, phosphorylation of TBK1 and IRF3 and cytoplasmic co-localization of STING and TBK1. M. bovis infection led to the interaction of activated IRF3 and cytoplasmic Bax leading to mitochondrial damage. Role of IRF3 in apoptosis was further confirmed by blocking this molecule with BX-795 that showed significant reduction expression of caspase-8 and caspase-3. Intracellular survival of M. bovis increased in response to 4-PBA and BX-795. These findings indicate that STING-TBK1-IRF3 pathway mediates a crosstalk between ER stress and apoptosis during M. bovis infection, which can effectively control intracellular bacteria.

show abstract

Imaging of single cell responses to ER stress indicates that the relative dynamics of IRE1/XBP1 and PERK/ATF4 signalling rather than a switch between signalling branches determine cell survival

Cited by 113 publications

References 33 publications

Serum glycomarkers of endoplasmic reticulum and lysosomal-endosomal system stress in human healthy aging and diseases

Serum glycomarkers of endoplasmic reticulum and lysosomal-endosomal system stress in human healthy aging and diseases

The Combination of Alcohol and Cigarette Smoke Induces Endoplasmic Reticulum Stress and Cell Death in Pancreatic Acinar Cells

Mycobacterium bovis Induces Endoplasmic Reticulum Stress Mediated-Apoptosis by Activating IRF3 in a Murine Macrophage Cell Line

Contact Info

Product

Resources

About