scholarly journals Hyperlipidemic hypersensitivity to lethal microbial inflammation and its reversal by selective targeting of nuclear transport shuttles

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yan Liu ◽  
Jozef Zienkiewicz ◽  
Kelli L. Boyd ◽  
Taylor E. Smith ◽  
Zhi-Qi Xu ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Binding Proteins ◽  
Nuclear Transport ◽  
Regulatory Element ◽  
Lethal Dose ◽  
Inflammatory Cells ◽  
Cytokines And Chemokines ◽  
Selective Targeting ◽  
Life Threatening ◽  
Responsive Element

AbstractHyperlipidemia, the hallmark of Metabolic Syndrome that afflicts millions of people worldwide, exacerbates life-threatening infections. We present a new evidence for the mechanism of hyperlipidemic hypersensitivity to microbial inflammation caused by pathogen-derived inducer, LPS. We demonstrate that hyperlipidemic animals succumbed to a non-lethal dose of LPS whereas normolipidemic controls survived. Strikingly, survival of hyperlipidemic animals was restored when the nuclear import of stress-responsive transcription factors (SRTFs), Sterol Regulatory Element-Binding Proteins (SREBPs), and Carbohydrate-Responsive Element-Binding Proteins (ChREBPs) was impeded by targeting the nuclear transport checkpoint with cell-penetrating, biselective nuclear transport modifier (NTM) peptide. Furthermore, the burst of proinflammatory cytokines and chemokines, microvascular endothelial injury in the liver, lungs, heart, and kidneys, and trafficking of inflammatory cells were also suppressed. To dissect the role of nuclear transport signaling pathways we designed and developed importin-selective NTM peptides. Selective targeting of the importin α5, ferrying SRTFs and ChREBPs, protected 70–100% hyperlipidemic animals. Targeting importin β1, that transports SREBPs, was only effective after 3-week treatment that lowered blood triglycerides, cholesterol, glucose, and averted fatty liver. Thus, the mechanism of hyperlipidemic hypersensitivity to lethal microbial inflammation depends on metabolic and proinflammatory transcription factors mobilization, which can be counteracted by targeting the nuclear transport checkpoint.

scholarly journals Overlapping Roles for Interleukin-36 Cytokines in Protective Host Defense against MurineLegionella pneumophilaPneumonia

2018 ◽  
Vol 87 (1) ◽  
Author(s):  
Yuta Nanjo ◽  
Michael W. Newstead ◽  
Tetsuji Aoyagi ◽  
Xianying Zeng ◽  
Kazuhisa Takahashi ◽  
...  
Keyword(s):  
Host Defense ◽  
Legionella Pneumophila ◽  
Ex Vivo ◽  
Inflammatory Cells ◽  
Bacterial Clearance ◽  
Content Type ◽  
Cytokines And Chemokines ◽  
M1 Polarization ◽  
Life Threatening ◽  
Deficient Mice

ABSTRACTLegionella pneumophilacauses life-threatening pneumonia culminating in acute lung injury. Innate and adaptive cytokines play an important role in host defense againstL. pneumophilainfection. Interleukin-36 (IL-36) cytokines are recently described members of the larger IL-1 cytokine family known to exert potent inflammatory effects. In this study, we elucidated the role for IL-36 cytokines in experimental pneumonia caused byL. pneumophila. Intratracheal (i.t.) administration ofL. pneumophilainduced the upregulation of both IL-36α and IL-36γ mRNA and protein production in the lung. Compared to the findings forL. pneumophila-infected wild-type (WT) mice, the i.t. administration ofL. pneumophilato IL-36 receptor-deficient (IL-36R−/−) mice resulted in increased mortality, a delay in lung bacterial clearance, increasedL. pneumophiladissemination to extrapulmonary organs, and impaired glucose homeostasis. Impaired lung bacterial clearance in IL-36R−/−mice was associated with a significantly reduced accumulation of inflammatory cells and the decreased production of proinflammatory cytokines and chemokines.Ex vivo, reduced expression of costimulatory molecules and impaired M1 polarization were observed in alveolar macrophages isolated from infected IL-36R−/−mice compared to macrophages from WT mice. WhileL. pneumophila-induced mortality in IL-36α- or IL-36γ-deficient mice was not different from that in WT animals, antibody-mediated neutralization of IL-36γ in IL-36α−/−mice resulted in mortality similar to that observed in IL-36R−/−mice, indicating redundant and overlapping roles for these cytokines in experimental murineL. pneumophilapneumonia.

scholarly journals Sterol Regulatory Element Binding Proteins in Fungi: Hypoxic Transcription Factors Linked to Pathogenesis

2010 ◽  
Vol 9 (3) ◽  
pp. 352-359 ◽  
Author(s):  
Clara M. Bien ◽  
Peter J. Espenshade
Keyword(s):  
Transcription Factors ◽  
Binding Proteins ◽  
Regulatory Element ◽  
Antifungal Drugs ◽  
Adaptation To Hypoxia ◽  
Human Pathogens ◽  
Low Oxygen ◽  
Proteolytic Activation ◽  
Content Type ◽  
Sterol Regulatory Element

ABSTRACT Sterol regulatory element binding proteins (SREBPs) are membrane-bound transcription factors whose proteolytic activation is controlled by the cellular sterol concentration. Mammalian SREBPs are activated in cholesterol-depleted cells and serve to regulate cellular lipid homeostasis. Recent work demonstrates that SREBP is functionally conserved in fungi. While the ability to respond to sterols is conserved, fungal SREBPs are hypoxic transcription factors required for adaptation to a low-oxygen environment. In the fission yeast Schizosaccharomyces pombe, oxygen regulates the SREBP homolog Sre1 by independently controlling both its proteolytic activation and its degradation. SREBP is also required for adaptation to hypoxia in the human pathogens Cryptococcus neoformans and Aspergillus fumigatus. In these organisms, SREBP is required for virulence and resistance to antifungal drugs, making the SREBP pathway a potential target for antifungal therapy.

scholarly journals Upc2p and Ecm22p, Dual Regulators of Sterol Biosynthesis in Saccharomyces cerevisiae

2001 ◽  
Vol 21 (19) ◽  
pp. 6395-6405 ◽  
Author(s):  
Åshild Vik ◽  
Jasper Rine
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Transcriptional Regulation ◽  
Transcription Factors ◽  
Binding Proteins ◽  
Regulatory Element ◽  
Human Cells ◽  
Sterol Biosynthesis ◽  
Sterol Synthesis ◽  
Binuclear Cluster ◽  
Sterol Regulatory Element

ABSTRACT Sterol levels affect the expression of many genes in yeast and humans. We found that the paralogous transcription factors Upc2p and Ecm22p of yeast were sterol regulatory element (SRE) binding proteins (SREBPs) responsible for regulating transcription of the sterol biosynthetic genes ERG2 and ERG3. We defined a 7-bp SRE common to these and other genes, including many genes involved in sterol biosynthesis. Upc2p and Ecm22p activatedERG2 expression by binding directly to this element in the ERG2 promoter. Upc2p and Ecm22p may thereby coordinately regulate genes involved in sterol homeostasis in yeast. Ecm22p and Upc2p are members of the fungus-specific Zn[2]-Cys[6] binuclear cluster family of transcription factors and share no homology to the analogous proteins, SREBPs, that are responsible for transcriptional regulation by sterols in humans. These results suggest that Saccharomyces cerevisiae and human cells regulate sterol synthesis by different mechanisms.

Transcription factors acting on the promoter of the rat fatty acid synthase gene

2002 ◽  
Vol 30 (6) ◽  
pp. 1070-1072 ◽  
Author(s):  
M. Schweizer ◽  
K. Roder ◽  
L. Zhang ◽  
S. S. Wolf
Keyword(s):  
Transcription Factors ◽  
Fatty Acid ◽  
Binding Sites ◽  
Fatty Acid Synthase ◽  
Regulatory Element ◽  
Upstream Stimulatory Factor ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Responsive Element ◽  
Stimulatory Factor

Fatty acid synthase (FAS), one of the main lipogenic enzymes, converts dietary calories into a storage form of energy. The transcription factors, stimulatory proteins 1 and 3 (Sp1 and Sp3), nuclear factor Y (NF-Y), upstream stimulatory factor (USF) and sterol regulatory element binding protein-1 (SREBP-1) have cognate binding sites on the promoter of the FAS gene. It was shown that Sp1 and NF-Y interact co-operatively at the diet-induced DNase I-hypersensitive site at position —500. Adjacent binding sites for NF-Y and Sp1 have also been found between —71 and —52, and —91 and —83. cAMP regulation is mediated via the inverted CAAT element (ICE) at —99 to —92, which binds NF-Y. The FAS insulin-responsive element 3 (FIRE3)-binding site at —71 to —52 is capable of binding NF-Y, USF and SREBP-1, and is required for the sterol response in conjunction with the co-activator NF-Y around —100. Surprisingly, both FIRE3 and ICE are also necessary for the response to retinoic acid that plays a role in development and is an essential component of the diet.

scholarly journals Regulation of the interleukin-2 CD28-responsive element by NF-ATp and various NF-kappaB/Rel transcription factors.

1997 ◽  
Vol 17 (5) ◽  
pp. 2605-2614 ◽  
Author(s):  
S B Maggirwar ◽  
E W Harhaj ◽  
S C Sun
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
Gene Transcription ◽  
Binding Proteins ◽  
Interleukin 2 ◽  
Activated T Cells ◽  
Costimulatory Signal ◽  
Enhancer Binding Proteins ◽  
Nf Kappab ◽  
Responsive Element

The CD28 costimulatory signal enhances antigen-mediated induction of interleukin-2 (IL-2) gene transcription through activation of an enhancer termed the CD28-responsive element (CD28RE). Although various nuclear proteins have been shown to bind to CD28RE, their in vivo functions in the regulation of this enhancer remain elusive. In this report, we show that CD28RE binds distinct transcription factors in cells treated with different mitogenic stimuli. Stimulation of the T-cell receptor (TCR) complex in the absence of a CD28 costimulatory signal induces a member of the nuclear factor of the activated T cells, NF-ATp; however, this treatment fails to activate the CD28RE enhancer activity. Significant activation of CD28RE was detected when the cells were treated with both the TCR stimulators and an anti-CD28 monoclonal antibody (anti-CD28), which induces the NF-kappaB/Rel enhancer binding proteins in addition to NF-ATp. The costimulatory activity of anti-CD28 can be further enhanced by a phorbol ester. Kinetic analyses demonstrate that activation of endogenous IL-2 gene transcription is correlated with the binding of CD28RE by NF-ATp and different NF-kappaB/Rel species. Transient-transfection studies reveal that expression of either NF-ATp or the p50-RelA NF-kappaB heterodimer leads to the potent transactivation of both the CD28RE enhancer and the intact IL-2 promoter in mitogen-stimulated cells. Remarkably, coexpression of these two families of enhancer-binding proteins in Jurkat T cells results in the transactivation of the CD28RE enhancer even in the absence of any cellular stimuli. Together, these results suggest that activation of IL-2 gene transcription by the TCR- and CD28-mediated signals involves the interaction of CD28RE with NF-ATp and various NF-kappaB/Rel transcription factors.

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