scholarly journals Conditional gene expression reveals stage‐specific functions of the unfolded protein response in the Ustilago maydis– maize pathosystem

2019 ◽  
Vol 21 (2) ◽  
pp. 258-271 ◽  
Author(s):  
Lara Schmitz ◽  
James W. Kronstad ◽  
Kai Heimel
Keyword(s):  
Gene Expression ◽  
Unfolded Protein Response ◽  
Ustilago Maydis ◽  
Unfolded Protein ◽  
Conditional Gene Expression ◽  
The Unfolded Protein Response ◽  
Protein Response

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 The Unfolded Protein Response Regulates Pathogenic Development of Ustilago maydis by Rok1-Dependent Inhibition of Mating-Type Signaling

mBio ◽  
2019 ◽  
Vol 10 (6) ◽  
Author(s):  
Lara Schmitz ◽  
Melina Ayaka Schwier ◽  
Kai Heimel
Keyword(s):  
Unfolded Protein Response ◽  
Mating Type ◽  
Ustilago Maydis ◽  
Mitogen Activated Protein Kinase ◽  
In Planta ◽  
Fungal Virulence ◽  
Content Type ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

ABSTRACT Fungal pathogens require the unfolded protein response (UPR) to maintain protein homeostasis of the endoplasmic reticulum (ER) during pathogenic development. In the corn smut fungus Ustilago maydis, pathogenic development is controlled by the a and b mating-type loci. The UPR is specifically activated after plant penetration and required for efficient secretion of effectors and suppression of the plant defense response. The interaction between the UPR regulator Cib1 and the central developmental regulator Clp1 modulates the pathogenic program and triggers fungal colonization of the host plant. By contrast, when activated before plant penetration, the UPR interferes with fungal virulence by reducing expression of bE and bW, the central regulators of pathogenic development encoded by the b mating-type locus. Here, we show that this inhibitory effect results from UPR-mediated suppression of the pheromone response pathway upstream of the b regulatory network. UPR activity prompts dephosphorylation of the pheromone-responsive mitogen-activated protein kinase (MAPK) Kpp2, reducing activity of the pheromone response factor Prf1 that regulates expression of bE and bW. Deletion of the dual specificity phosphatase rok1 fully suppressed UPR-dependent inhibition of Kpp2 phosphorylation, formation of infectious filaments, and fungal virulence. Rok1 determines the activity of mating-type signaling pathways and thus the degree of fungal virulence. We propose that UPR-dependent regulation of Rok1 aligns ER physiology with fungal aggressiveness and effector gene expression during biotrophic growth of U. maydis in the host plant. IMPORTANCE The unfolded protein response (UPR) is crucial for endoplasmic reticulum (ER) homeostasis and disease development in fungal pathogens. In the plant-pathogenic fungus Ustilago maydis, the UPR supports fungal proliferation in planta and effector secretion for plant defense suppression. In this study, we uncovered that UPR activity, which is normally restricted to the biotrophic stage in planta, inhibits mating and the formation of infectious filaments by Rok1-dependent dephosphorylation of the pheromone responsive mitogen-activated protein kinase (MAPK) Kpp2. This observation is relevant for understanding how the fungal virulence program is regulated by cellular physiology. UPR-mediated control of mating-type signaling pathways predicts that effector gene expression and the virulence potential are controlled by ER stress levels.

scholarly journals Signal peptide peptidase activity connects the unfolded protein response to plant defense suppression by Ustilago maydis

2019 ◽  
Vol 15 (4) ◽  
pp. e1007734 ◽  
Author(s):  
Niko Pinter ◽  
Christina Andrea Hach ◽  
Martin Hampel ◽  
Dmitrij Rekhter ◽  
Krzysztof Zienkiewicz ◽  
...  
Keyword(s):  
Plant Defense ◽  
Unfolded Protein Response ◽  
Signal Peptide ◽  
Ustilago Maydis ◽  
Peptidase Activity ◽  
Signal Peptide Peptidase ◽  
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

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.

The Unfolded Protein Response Is a Determinant of Disease Actvity in Waldenstrom’s Macroglobulinemia (WM).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 996-996
Author(s):  
Xavier Leleu ◽  
Lian Xu ◽  
Daniel D. Santos ◽  
Allen W. Ho ◽  
Zachary R. Hunter ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Waldenström’S Macroglobulinemia ◽  
Unfolded Protein ◽  
Waldenstrom's Macroglobulinemia ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Waldenström's Macroglobulinemia

Abstract The unfolded protein response (UPR) maintains the quality of newly synthesized secretory and transmembrane proteins such as immunoglobulins in the endoplasmic reticulum (ER) of eukaryotic cells. The most proximal sensors of the UPR are the ATF6, IRE1a-Xbp1, and PERK proteins. Bip, an ER stress-induced pro-survival molecular chaperone, controls the trafficking of Atf6 and is considered as an indicator of the onset of the UPR. EDEM, downstream of Xbp1 splicing, regulates the extraction of misfolded proteins into the cytosol for proteasome-mediated destruction. Ultimately, the initially cytoprotective UPR triggers an apoptotic cascade if ER stress is not corrected. We studied the UPR stress system in patients with Waldenstrom’s Macroglobulinemia (WM), a B-cell disorder characterized by excess secretion of IgM. As part of these efforts, we examined the UPR genes Bip-Atf6, Ire1a-Xbp1, Perk, as well as genes downstream of the UPR pathway including Xbp1 spliced-Edem, eIF2a and Gadd34 using semi-quantitative PCR analysis of CD19+ selected bone marrow lymphoplasmacytic cells (LPC) from 46 patients with the consensus panel diagnosis of WM. We found that UPR gene expression was highly heterogeneous with 16 (35%) patients expressing all genes, whilst 11 patients (24%) expressed only Xbp1 and Edem. Among patients expressing all UPR genes, median serum IgM (p=0.025) and B2M (p=0.05) levels, as well as bone marrow involvement (p=0.06) were higher, with levels of Bip showing greatest correlation to serum IgM and B2M levels, and BM involvement (p=0.01). These results confirm that UPR gene expression is related to disease activity in WM, and suggest a particular role for Bip as a prognostic factor in this disease.

scholarly journals Transcription factor ATF4 directs basal and stress-induced gene expression in the unfolded protein response and cholesterol metabolism in the liver

2016 ◽  
Vol 27 (9) ◽  
pp. 1536-1551 ◽  
Author(s):  
Michael E. Fusakio ◽  
Jeffrey A. Willy ◽  
Yongping Wang ◽  
Emily T. Mirek ◽  
Rana J. T. Al Baghdadi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Transcription Factor ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Cholesterol Metabolism ◽  
Unfolded Protein ◽  
Expression Of Genes ◽  
The Unfolded Protein Response ◽  
Protein Response

Disturbances in protein folding and membrane compositions in the endoplasmic reticulum (ER) elicit the unfolded protein response (UPR). Each of three UPR sensory proteins—PERK (PEK/EIF2AK3), IRE1, and ATF6—is activated by ER stress. PERK phosphorylation of eIF2 represses global protein synthesis, lowering influx of nascent polypeptides into the stressed ER, coincident with preferential translation of ATF4 (CREB2). In cultured cells, ATF4 induces transcriptional expression of genes directed by the PERK arm of the UPR, including genes involved in amino acid metabolism, resistance to oxidative stress, and the proapoptotic transcription factor CHOP (GADD153/DDIT3). In this study, we characterize whole-body and tissue-specific ATF4-knockout mice and show in liver exposed to ER stress that ATF4 is not required for CHOP expression, but instead ATF6 is a primary inducer. RNA-Seq analysis indicates that ATF4 is responsible for a small portion of the PERK-dependent UPR genes and reveals a requirement for expression of ATF4 for expression of genes involved in oxidative stress response basally and cholesterol metabolism both basally and under stress. Consistent with this pattern of gene expression, loss of ATF4 resulted in enhanced oxidative damage, and increased free cholesterol in liver under stress accompanied by lowered cholesterol in sera.

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