Unfolded protein response (UPR) gene expression during antibody-dependent enhanced infection of cultured monocytes correlates with dengue disease severity

DENV (dengue virus) induces UPR (unfolded protein response) in the host cell, which strikes a balance between pro-survival and pro-apoptotic signals. We previously showed that Salubrinal, a drug that targets the UPR, inhibits DENV replication. Here, we examine the impact on UPR after direct or ADE (antibody-dependent enhanced) infection of cells with DENV clinical isolates. THP-1 cells in the presence of subneutralizing concentration of humanized antibody 4G2 (cross-reactive with flavivirus envelope protein) or HEK-293 cells (human embryonic kidney 293 cells) were infected with DENV-1–4 serotypes. UPR gene expression was monitored under these infection conditions using real-time RT–PCR (reverse transcription–PCR) and Western blots to analyse serotype-dependent variations. Subsequently, in a blinded study, strain-specific differences were compared between DENV-2 clinical isolates obtained from a single epidemic. Results showed that THP-1 cells were infected efficiently and equally by DENV-1–4 in the ADE mode. At 48 hpi (h post infection), DENV-1 and -3 showed a higher replication rate and induced higher expression of several UPR genes such as BiP (immunoglobulin heavy-chain-binding protein), GADD34 (growth arrest DNA damage-inducible protein 34) and CHOP [C/EBP (CCAAT/enhancer-binding protein)-homologous protein]. The ADE infection of THP-1 cells with epidemic DENV-2 high-UPR-gene-expressing strains appears to correlate with severe disease; however, no such correlation could be made when the same viruses were used to infect HEK-293 cells. Our finding that UPR gene expression in THP-1 cells during ADE infection correlates with dengue disease severity is consistent with a previous study [Morens, Marchette, Chu and Halstead (1991) Am. J. Trop. Med. Hyg. 45, 644–651] that showed that the growth of DENV 2 isolates in human peripheral blood leucocytes correlated with severe and mild dengue diseases.

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Faculty Opinions recommendation of The unfolded protein response modulates disease severity in Pelizaeus-Merzbacher disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1007041.165807 ◽

2002 ◽

Author(s):

David Ron

Keyword(s):

Unfolded Protein Response ◽

Disease Severity ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response ◽

Pelizaeus Merzbacher Disease

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Transcriptome Analysis of Recombinant Protein Secretion by Aspergillus nidulans and the Unfolded-Protein Response In Vivo

Applied and Environmental Microbiology ◽

10.1128/aem.71.5.2737-2747.2005 ◽

2005 ◽

Vol 71 (5) ◽

pp. 2737-2747 ◽

Cited By ~ 61

Author(s):

Andrew H. Sims ◽

Manda E. Gent ◽

Karin Lanthaler ◽

Nigel S. Dunn-Coleman ◽

Stephen G. Oliver ◽

...

Keyword(s):

Gene Expression ◽

Recombinant Protein ◽

Unfolded Protein Response ◽

Aspergillus Nidulans ◽

Filamentous Fungi ◽

Protein Secretion ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

ABSTRACT Filamentous fungi have a high capacity for producing large amounts of secreted proteins, a property that has been exploited for commercial production of recombinant proteins. However, the secretory pathway, which is key to the production of extracellular proteins, is rather poorly characterized in filamentous fungi compared to yeast. We report the effects of recombinant protein secretion on gene expression levels in Aspergillus nidulans by directly comparing a bovine chymosin-producing strain with its parental wild-type strain in continuous culture by using expressed sequence tag microarrays. This approach demonstrated more subtle and specific changes in gene expression than those observed when mimicking the effects of protein overproduction by using a secretion blocker. The impact of overexpressing a secreted recombinant protein more closely resembles the unfolded-protein response in vivo.

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Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the unfolded protein response (UPR) in models of neurodegeneration

10.1101/2020.11.17.387480 ◽

2020 ◽

Author(s):

René L. Vidal ◽

Denisse Sepulveda ◽

Paulina Troncoso-Escudero ◽

Paula Garcia-Huerta ◽

Constanza Gonzalez ◽

...

Keyword(s):

Gene Expression ◽

Unfolded Protein Response ◽

Target Genes ◽

Cell Function ◽

Alpha Synuclein ◽

Protective Effects ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

AbstractAlteration to endoplasmic reticulum (ER) proteostasis is observed on a variety of neurodegenerative diseases associated with abnormal protein aggregation. Activation of the unfolded protein response (UPR) enables an adaptive reaction to recover ER proteostasis and cell function. The UPR is initiated by specialized stress sensors that engage gene expression programs through the concerted action of the transcription factors ATF4, ATF6f, and XBP1s. Although UPR signaling is generally studied as unique linear signaling branches, correlative evidence suggests that ATF6f and XBP1s may physically interact to regulate a subset of UPR-target genes. Here, we designed an ATF6f-XBP1s fusion protein termed UPRplus that behaves as a heterodimer in terms of its selective transcriptional activity. Cell-based studies demonstrated that UPRplus has stronger an effect in reducing the abnormal aggregation of mutant huntingtin and alpha-synuclein when compared to XBP1s or ATF6 alone. We developed a gene transfer approach to deliver UPRplus into the brain using adeno-associated viruses (AAVs) and demonstrated potent neuroprotection in vivo in preclinical models of Parkinson’s and Huntington’s disease. These results support the concept where directing UPR-mediated gene expression toward specific adaptive programs may serve as a possible strategy to optimize the beneficial effects of the pathway in different disease conditions.

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PERK/eIF2α signaling inhibits HIF-induced gene expression during the unfolded protein response via YB1-dependent regulation of HIF1α translation

Nucleic Acids Research ◽

10.1093/nar/gky127 ◽

2018 ◽

Vol 46 (8) ◽

pp. 3878-3890 ◽

Cited By ~ 11

Author(s):

Iglika G Ivanova ◽

Catherine V Park ◽

Adrian I Yemm ◽

Niall S Kenneth

Keyword(s):

Gene Expression ◽

Unfolded Protein Response ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

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Development and validation of an unfolded protein response-related gene signature to predict overall survival in HNSCC.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e18033 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e18033-e18033

Author(s):

Jun Chen ◽

Bei Zhang

Keyword(s):

Gene Expression ◽

Overall Survival ◽

Unfolded Protein Response ◽

Cox Regression ◽

Risk Group ◽

Gene Signature ◽

Related Gene ◽

Hallmarks Of Cancer ◽

Unfolded Protein ◽

Protein Response

e18033 Background: Genomic expression profiles have enabled the classification of head and neck squamous cell carcinoma (HNSCC) into molecular sub-types and provide prognostic information, which have implications for the personalized treatment of HNSCC beyond clinical and pathological features. Methods: Gene-expression profiling was identified in TCGA- HNSCC (n = 492) and validated with the Gene Expression Ominibus (GEO) dataset(n = 270) for which RNA sequencing data and clinical covariates were available. A single-sample gene set enrichment analysis (ssGSEA) algorithm were used to quantified the levels of various hallmarks of cancer. And LASSO Cox regression model was used to screen robust prognostic biomarkers to identify the best set of survival-associated gene signatures in HNSCC. Statistical analyses were performed using R version 3.4.4. Results: We identified unfolded protein response as the primary risk factor for survival（cox coefficient = 17.4 [8.4-26.3], P < 0.001）among various hallmarks of cancer in TCGA- HNSCC. And unfolded protein response ssGESA scores were significantly elevated in patients who died during follow up (P = 0.009). Kaplan-Meier analysis showed that patients with low ssGSEA scores of unfolded protein response exhibited better OS (HR = 0.69, P = 0.008). And we established an unfolded protein response-related gene signature based on lasso cox. We then apply the unfolded protein response -related gene signature to classify patients into the high risk group and the low risk group with the cutoff of 0.18. Adjusted for stage，age，gender, our signature was an independent risk factor for overall survival in TCGA cohorts (HR = 0.39 [0.28-0.53],P = < 0.001). In external independent cohorts, similar results were observed. In the validation cohort GEO65858, the patients with high unfolded protein response score showed longer survival (HR = 0.62 [0.38-1.0], P = 0.049). And adjusted for stage，age，HPV state, the multivariate cox regression analysis showed that unfolded protein response-related gene signature exhibited an independent risk prediction for overall survival in 270 patients with HNSCC (HR = 0.57 [0.35-0.94], P = 0.026). Conclusions: By analyzing the gene-expression data with bioinformation approach, we developed and validated a risk prediction model with unfolded protein response -related expression scores in HNSCC, which have the potential to identify patients who could have better overall survival.

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