scholarly journals Repression of Viral Gene Expression and Replication by the Unfolded Protein Response Effector XBP1u

2019 ◽  
Author(s):  
Florian Hinte ◽  
Eelco van Anken ◽  
Boaz Tirosh ◽  
Wolfram Brune
Keyword(s):  
Gene Expression ◽  
Life Cycle ◽  
Unfolded Protein Response ◽  
Viral Gene Expression ◽  
Murine Cytomegalovirus ◽  
Viral Gene ◽  
Unfolded Protein ◽  
Xbp1 Mrna ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractThe unfolded protein response (UPR) is a cellular homeostatic circuit regulating protein synthesis and processing in the ER by three ER-to-nucleus signaling pathways. One pathway is triggered by the inositol-requiring enzyme 1 (IRE1), which splices the X-box binding protein 1 (XBP1) mRNA, thereby enabling expression of XBP1s. Another UPR pathway activates the activating transcription factor 6 (ATF6). Here we show that murine cytomegalovirus (MCMV), a prototypic β-herpesvirus, harnesses the UPR to regulate its own life cycle. MCMV activates the IRE1-XBP1 pathway early post infection to relieve repression by XBP1u, the product of the unspliced XBP1 mRNA. XBP1u inhibits viral gene expression and replication by blocking the activation of the viral major immediate-early promoter by XBP1s and ATF6. These findings reveal a redundant function of XBP1s and ATF6 as activators of the viral life cycle, and an unexpected role of XBP1u as a potent repressor of both XBP1s and ATF6-mediated activation.

scholarly journals Repression of viral gene expression and replication by the unfolded protein response effector XBP1u

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Florian Hinte ◽  
Eelco van Anken ◽  
Boaz Tirosh ◽  
Wolfram Brune
Keyword(s):  
Gene Expression ◽  
Life Cycle ◽  
Unfolded Protein Response ◽  
Viral Gene Expression ◽  
Murine Cytomegalovirus ◽  
Viral Gene ◽  
Unfolded Protein ◽  
Xbp1 Mrna ◽  
The Unfolded Protein Response ◽  
Protein Response

The unfolded protein response (UPR) is a cellular homeostatic circuit regulating protein synthesis and processing in the ER by three ER-to-nucleus signaling pathways. One pathway is triggered by the inositol-requiring enzyme 1 (IRE1), which splices the X-box binding protein 1 (Xbp1) mRNA, thereby enabling expression of XBP1s. Another UPR pathway activates the activating transcription factor 6 (ATF6). Here we show that murine cytomegalovirus (MCMV), a prototypic β-herpesvirus, harnesses the UPR to regulate its own life cycle. MCMV activates the IRE1-XBP1 pathway early post infection to relieve repression by XBP1u, the product of the unspliced Xbp1 mRNA. XBP1u inhibits viral gene expression and replication by blocking the activation of the viral major immediate-early promoter by XBP1s and ATF6. These findings reveal a redundant function of XBP1s and ATF6 as activators of the viral life cycle, and an unexpected role of XBP1u as a potent repressor of both XBP1s and ATF6-mediated activation.

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

2005 ◽  
Vol 71 (5) ◽  
pp. 2737-2747 ◽  
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.

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

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.

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

2018 ◽  
Vol 46 (8) ◽  
pp. 3878-3890 ◽  
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

scholarly journals Activation of the Unfolded Protein Response Pathway Induces Human Asparagine Synthetase Gene Expression

1999 ◽  
Vol 274 (44) ◽  
pp. 31139-31144 ◽  
Author(s):  
Ione P. Barbosa-Tessmann ◽  
Chin Chen ◽  
Can Zhong ◽  
Sheldon M. Schuster ◽  
Harry S. Nick ◽  
...  
Keyword(s):  
Gene Expression ◽  
Unfolded Protein Response ◽  
Asparagine Synthetase ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Ire1 regulated XBP1 mRNA splicing is essential for the unfolded protein response (UPR) in Drosophila melanogaster

2007 ◽  
Vol 354 (3) ◽  
pp. 789-794 ◽  
Author(s):  
Nongluk Plongthongkum ◽  
Niwed Kullawong ◽  
Sakol Panyim ◽  
Witoon Tirasophon
Keyword(s):  
Drosophila Melanogaster ◽  
Unfolded Protein Response ◽  
Mrna Splicing ◽  
Unfolded Protein ◽  
Xbp1 Mrna ◽  
The Unfolded Protein Response ◽  
Protein Response
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