scholarly journals An unfolded protein response is the initial cellular response to the expression of mutant matrilin-3 in a mouse model of multiple epiphyseal dysplasia

2010 ◽  
Vol 15 (6) ◽  
pp. 835-849 ◽  
Author(s):  
Seema Nundlall ◽  
M. Helen Rajpar ◽  
Peter A. Bell ◽  
Christopher Clowes ◽  
Leo A. H. Zeeff ◽  
...  
Keyword(s):  
Mouse Model ◽  
Unfolded Protein Response ◽  
Cellular Response ◽  
Multiple Epiphyseal Dysplasia ◽  
Unfolded Protein ◽  
Epiphyseal Dysplasia ◽  
Protein Response

scholarly journals Transcriptome Analysis Reveals Unfolded Protein Response Was Induced During the Early Stage of Burkholderia pseudomallei Infection in A549 Cells

2020 ◽  
Vol 11 ◽  
Author(s):  
Chenglong Rao ◽  
Chan Mao ◽  
Yupei Xia ◽  
Meijuan Zhang ◽  
Zhiqiang Hu ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Burkholderia Pseudomallei ◽  
Cellular Response ◽  
A549 Cells ◽  
Lung Epithelial Cells ◽  
Response Dynamics ◽  
Unfolded Protein ◽  
Lung Epithelial ◽  
Protein Response ◽  
Over Time

Burkholderia pseudomallei is a zoonotic pathogen that usually affects patients' lungs and causes serious melioidosis. The interaction of B. pseudomallei with its hosts is complex, and cellular response to B. pseudomallei infection in humans still remains to be elucidated. In this study, transcriptomic profiling of B. pseudomallei-infected human lung epithelial A549 cells was performed to characterize the cellular response dynamics during the early infection (EI) stage. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed by using the online databases DAVID 6.8 and KOBAS 3.0. Real-time quantitative PCR and western blot were used for validation experiments. Compared with the negative control group (NC), a set of 36 common genes varied over time with a cut-off level of 1.5-fold change, and a P-value < 0.05 was identified. Bioinformatics analysis indicated that the PERK-mediated unfolded protein response (UPR) was enriched as the most noteworthy biological process category, which was enriched as a branch of UPR in the signaling pathway of protein processing in the endoplasmic reticulum. Other categories, such as inflammatory responses, cell migration, and apoptosis, were also focused. The molecular chaperone Bip (GRP78), PERK, and PERK sensor-dependent phosphorylation of eIF2α (p-eIF2α) and ATF4 were verified to be increasing over time during the EI stage, suggesting that B. pseudomallei infection activated the PERK-mediated UPR in A549 cells. Collectively, these results provide important initial insights into the intimate interaction between B. pseudomallei and lung epithelial cells, which can be further explored toward the elucidation of the cellular mechanisms of B. pseudomallei infections in humans.

scholarly journals Hypoxia-induced SETX links replication stress with the unfolded protein response

2020 ◽  
Author(s):  
Shaliny Ramachandran ◽  
Tiffany Ma ◽  
Natalie Ng ◽  
Iosifina P. Foskolou ◽  
Ming-Shih Hwang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Unfolded Protein Response ◽  
Cellular Response ◽  
Biological Response ◽  
Transcriptional Response ◽  
Replication Stress ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Stress Dependent ◽  
Protein Response

ABSTRACTThe levels of hypoxia associated with resistance to radiotherapy significantly impact cancer patient prognosis. These levels of hypoxia initiate a unique transcriptional response with the rapid activation of numerous transcription factors in a background of global repression of transcription. Here, we show that the biological response to radiobiological hypoxia includes the induction of the DNA/RNA helicase SETX. In the absence of hypoxia-induced SETX, R-loop levels increase, DNA damage accumulates, and DNA replication rates decrease. SETX plays a key role in protecting cells from DNA damage induced during transcription in hypoxia. Importantly, we show that the mechanism of SETX induction is reliant on the PERK/ATF4 arm of the unfolded protein response. These data not only highlight the unique cellular response to radiobiological hypoxia, which includes both a replication stress dependent DNA damage response and an unfolded protein response but uncover a novel link between these two distinct pathways.

scholarly journals An Emerging Role for the Unfolded Protein Response in Pancreatic Cancer

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 261
Author(s):  
Claire M. Robinson ◽  
Aaron Talty ◽  
Susan E. Logue ◽  
Katarzyna Mnich ◽  
Adrienne M. Gorman ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Unfolded Protein Response ◽  
Cellular Response ◽  
Tumour Microenvironment ◽  
Pancreatic Stellate Cells ◽  
Paracrine Signalling ◽  
Unfolded Protein ◽  
Pancreatic Cancer Cells ◽  
The Unfolded Protein Response ◽  
Protein Response

Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer and one of the leading causes of cancer-associated deaths in the world. It is characterised by dismal response rates to conventional therapies. A major challenge in treatment strategies for PDAC is the presence of a dense stroma that surrounds the tumour cells, shielding them from treatment. This unique tumour microenvironment is fuelled by paracrine signalling between pancreatic cancer cells and supporting stromal cell types including the pancreatic stellate cells (PSC). While our molecular understanding of PDAC is improving, there remains a vital need to develop effective, targeted treatments. The unfolded protein response (UPR) is an elaborate signalling network that governs the cellular response to perturbed protein homeostasis in the endoplasmic reticulum (ER) lumen. There is growing evidence that the UPR is constitutively active in PDAC and may contribute to the disease progression and the acquisition of resistance to therapy. Given the importance of the tumour microenvironment and cytokine signalling in PDAC, and an emerging role for the UPR in shaping the tumour microenvironment and in the regulation of cytokines in other cancer types, this review explores the importance of the UPR in PDAC biology and its potential as a therapeutic target in this disease.

scholarly journals Regulated IRE1-dependent decay pathway is activated during Japanese encephalitis virus-induced unfolded protein response and benefits viral replication

2014 ◽  
Vol 95 (1) ◽  
pp. 71-79 ◽  
Author(s):  
Sankar Bhattacharyya ◽  
Utsav Sen ◽  
Sudhanshu Vrati
Keyword(s):  
Japanese Encephalitis Virus ◽  
Unfolded Protein Response ◽  
Japanese Encephalitis ◽  
Mammalian Cells ◽  
Cellular Response ◽  
Encephalitis Virus ◽  
Host Cells ◽  
Rnase Activity ◽  
Unfolded Protein ◽  
Protein Response

Japanese encephalitis virus (JEV) infection-induced encephalitis causes extensive death or long-term neurological damage, especially among children, in south and south-east Asia. Infection of mammalian cells has shown induction of an unfolded protein response (UPR), presumably leading to programmed cell death or apoptosis of the host cells. UPR, a cellular response to accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) lumen, is initiated by three ER-lumen-resident sensors (PERK, IRE1 and ATF6), and involves transcriptional and translational regulation of the expression of several genes. The sensor IRE1 possesses an intrinsic RNase activity, activated through homo-dimerization and autophosphorylation during UPR. Activated IRE1 performs cytoplasmic cleavage of Xbp1u transcripts, thus facilitating synthesis of XBP1S transcription factor, in addition to cleavage of a cohort of cellular transcripts, the later initiating the regulated IRE1-dependent decay (RIDD) pathway. In this study, we report the initiation of the RIDD pathway in JEV-infected mouse neuroblastoma cells (Neuro2a) and its effect on viral infection. Activation of the RIDD pathway led to degradation of known mouse cell target transcripts without showing any effect on JEV RNA despite the fact that both when biochemically purified showed significant enrichment in ER membrane-enriched fractions. Additionally, inhibition of the IRE1 RNase activity by STF083010, a specific drug, diminished viral protein levels and reduced the titre of the virus produced from infected Neuro2a cells. The results present evidence for the first report of a beneficial effect of RIDD activation on the viral life cycle.

scholarly journals Pathogenic tau does not drive activation of the unfolded protein response

2019 ◽  
Vol 294 (25) ◽  
pp. 9679-9688 ◽  
Author(s):  
Aleksandra P. Pitera ◽  
Ayodeji A. Asuni ◽  
Vincent O'Connor ◽  
Katrin Deinhardt
Keyword(s):  
Endoplasmic Reticulum ◽  
Mouse Model ◽  
Neurodegenerative Diseases ◽  
Unfolded Protein Response ◽  
Neuronal Cultures ◽  
Critical Determinant ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

The unfolded protein response (UPR) is commonly associated with a range of neurodegenerative diseases, and targeting UPR components has been suggested as a therapeutic strategy. The UPR surveys protein folding within the endoplasmic reticulum. However, many of the misfolded proteins that accumulate in neurodegeneration are localized so that they do not directly cause endoplasmic reticulum triggers that activate this pathway. Here, using a transgenic mouse model and primary cell cultures along with quantitative PCR, immunoblotting, and immunohistochemistry, we tested whether the UPR is induced in in vivo and in vitro murine models of tauopathy that are based on expression of mutant tauP301L. We found no evidence for the UPR in the rTg4510 mouse model, in which mutant tau is transgenically expressed under the control of tetracycline-controlled transactivator protein. This observation was supported by results from acute experiments in which neuronal cultures expressed mutant tau and accumulated misfolded cytoplasmic tau aggregates but exhibited no UPR activation. These results suggest that the UPR is not induced as a response to tau misfolding and aggregation despite clear evidence for progressive cellular dysfunction and degeneration. We propose that caution is needed when evaluating the implied significance of the UPR as a critical determinant across major neurodegenerative diseases.

scholarly journals Flavivirus Infection Activates the XBP1 Pathway of the Unfolded Protein Response To Cope with Endoplasmic Reticulum Stress

2006 ◽  
Vol 80 (23) ◽  
pp. 11868-11880 ◽  
Author(s):  
Chia-Yi Yu ◽  
Yun-Wei Hsu ◽  
Ching-Len Liao ◽  
Yi-Ling Lin
Keyword(s):  
Endoplasmic Reticulum ◽  
Unfolded Protein Response ◽  
Cellular Response ◽  
Nonstructural Protein ◽  
Hydrophobic Membrane ◽  
Potent Inducer ◽  
Unfolded Protein ◽  
Virus Serotype ◽  
The Unfolded Protein Response ◽  
Protein Response

ABSTRACT The unfolded protein response (UPR) is a coordinated change in gene expression triggered by perturbations in functions of the endoplasmic reticulum (ER). XBP1, a key transcription factor of the UPR, is activated by an IRE1-mediated splicing event, which results in a frameshift and encodes a protein with transcriptional activity. Here, we report that XBP1 was activated during flaviviral infection, as evidenced by XBP1 mRNA splicing and protein expression, as well as induction of the downstream genes ERdj4, EDEM1, and p58(IPK) in Japanese encephalitis virus (JEV)- and dengue virus serotype 2 (DEN-2)-infected cells. Reporter systems based on IRE1-mediated XBP1 splicing were established, and several flaviviral proteins associated with the ER, including glycoproteins and small hydrophobic membrane-anchored proteins, were found to trigger the splicing event. Notably, nonstructural protein NS2B-3 of DEN-2, but not of JEV, was a potent inducer of XBP1 splicing through an unclear mechanism(s). Reduction of XBP1 by a small interfering RNA had no effect on cells' susceptibility to the two viruses but exacerbated the flavivirus-induced cytopathic effects. Overall, flaviviruses trigger the XBP1 signaling pathway and take advantage of this cellular response to alleviate virus-induced cytotoxicity.

scholarly journals The Unfolded Protein Response and Autophagy on the Crossroads of Coronaviruses Infections

2021 ◽  
Vol 11 ◽  
Author(s):  
Elisa B. Prestes ◽  
Julia C. P. Bruno ◽  
Leonardo H. Travassos ◽  
Leticia A. M. Carneiro
Keyword(s):  
Viral Replication ◽  
Unfolded Protein Response ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Cellular Stress ◽  
Membrane Vesicles ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

The ability to sense and adequately respond to variable environmental conditions is central for cellular and organismal homeostasis. Eukaryotic cells are equipped with highly conserved stress-response mechanisms that support cellular function when homeostasis is compromised, promoting survival. Two such mechanisms – the unfolded protein response (UPR) and autophagy – are involved in the cellular response to perturbations in the endoplasmic reticulum, in calcium homeostasis, in cellular energy or redox status. Each of them operates through conserved signaling pathways to promote cellular adaptations that include re-programming transcription of genes and translation of new proteins and degradation of cellular components. In addition to their specific functions, it is becoming increasingly clear that these pathways intersect in many ways in different contexts of cellular stress. Viral infections are a major cause of cellular stress as many cellular functions are coopted to support viral replication. Both UPR and autophagy are induced upon infection with many different viruses with varying outcomes – in some instances controlling infection while in others supporting viral replication and infection. The role of UPR and autophagy in response to coronavirus infection has been a matter of debate in the last decade. It has been suggested that CoV exploit components of autophagy machinery and UPR to generate double-membrane vesicles where it establishes its replicative niche and to control the balance between cell death and survival during infection. Even though the molecular mechanisms are not fully elucidated, it is clear that UPR and autophagy are intimately associated during CoV infections. The current SARS-CoV-2 pandemic has brought renewed interest to this topic as several drugs known to modulate autophagy – including chloroquine, niclosamide, valinomycin, and spermine – were proposed as therapeutic options. Their efficacy is still debatable, highlighting the need to better understand the molecular interactions between CoV, UPR and autophagy.

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