Guanylate-binding proteins (GBPs) have recently emerged as central orchestrators of immunity to infection, inflammation, and neoplastic diseases. Within numerous host cell types, these IFN-induced GTPases assemble into large nanomachines that execute distinct host defense activities against a wide variety of microbial pathogens. In addition, GBPs customize inflammasome responses to bacterial infection and sepsis, where they act as critical rheostats to amplify innate immunity and regulate tissue damage. Similar functions are becoming evident for metabolic inflammatory syndromes and cancer, further underscoring the importance of GBPs within infectious as well as altered homeostatic settings. A better understanding of the basic biology of these IFN-induced GTPases could thus benefit clinical approaches to a wide spectrum of important human diseases.

/pdf/interferon-induced-guanylate-binding-proteins-guardians-of-ndjwdfjr2a.pdf

Interferon-induced guanylate-binding proteins: Guardians of host defense in health and disease.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with rising incidence. Diseased tissues are heavily vascularized. Surprisingly, the pathogenic impact of the vasculature in IBD and the underlying regulatory mechanisms remain largely unknown. IFN-γ is a major cytokine in IBD pathogenesis, but in the context of the disease, it is almost exclusively its immune-modulatory and epithelial cell-directed functions that have been considered. Recent studies by our group demonstrated that IFN-γ also exerts potent effects on blood vessels. Based on these considerations, we analyzed the vessel-directed pathogenic functions of IFN-γ and found that it drives IBD pathogenesis through vascular barrier disruption. Specifically, we show that inhibition of the IFN-γ response in vessels by endothelial-specific knockout of IFN-γ receptor 2 ameliorates experimentally induced colitis in mice. IFN-γ acts pathogenic by causing a breakdown of the vascular barrier through disruption of the adherens junction protein VE-cadherin. Notably, intestinal vascular barrier dysfunction was also confirmed in human IBD patients, supporting the clinical relevance of our findings. Treatment with imatinib restored VE-cadherin/adherens junctions, inhibited vascular permeability, and significantly reduced colonic inflammation in experimental colitis. Our findings inaugurate the pathogenic impact of IFN-γ-mediated intestinal vessel activation in IBD and open new avenues for vascular-directed treatment of this disease.

/pdf/ifn-g-drives-inflammatory-bowel-disease-pathogenesis-through-2ex31ghlxo.pdf

IFN-γ drives inflammatory bowel disease pathogenesis through VE-cadherin–directed vascular barrier disruption

Regulation of innate immune functions by guanylate-binding proteins.

Guanylate-binding protein 1 (GBP1) is a large GTPase of the dynamin superfamily involved in the regulation of membrane, cytoskeleton, and cell cycle progression dynamics. In many cell types, such as endothelial cells and monocytes, GBP1 expression is strongly provoked by interferon γ (IFNγ) and acts to restrain cellular proliferation in inflammatory contexts. In immunity, GBP1 activity is crucial for the maturation of autophagosomes infected by intracellular pathogens and the cellular response to pathogen-associated molecular patterns. In chronic inflammation, GBP1 activity inhibits endothelial cell proliferation even as it protects from IFNγ-induced apoptosis. A similar inhibition of proliferation has also been found in some tumor models, such as colorectal or prostate carcinoma mouse models. However, this activity appears to be context-dependent, as in other cancers, such as oral squamous cell carcinoma and ovarian cancer, GBP1 activity appears to anchor a complex, taxane chemotherapy resistance profile where its expression levels correlate with worsened prognosis in patients. This discrepancy in GBP1 function may be resolved by GBP1's involvement in the induction of a cellular senescence phenotype, wherein anti-proliferative signals coincide with potent resistance to apoptosis and set the stage for dysregulated proliferative mechanisms present in growing cancers to hijack GBP1 as a pro- chemotherapy treatment resistance (TXR) and pro-survival factor even in the face of continued cytotoxic treatment. While the structure of GBP1 has been extensively characterized, its roles in inflammation, TXR, senescence, and other biological functions remain under-investigated, although initial findings suggest that GBP1 is a compelling target for therapeutic intervention in a variety of conditions ranging from chronic inflammatory disorders to cancer.

/pdf/guanylate-binding-protein-1-an-emerging-target-in-981ee919go.pdf

Guanylate-Binding Protein 1: An Emerging Target in Inflammation and Cancer.

Human GBP1 Differentially Targets Salmonella and Toxoplasma to License Recognition of Microbial Ligands and Caspase-Mediated Death

Summary
In modern industrial production lines various process and material parameters determine the properties of the final product. Thus, a process optimization procedure has to take into account a large design space containing several parameters. As a consequence, the evaluation of the influence of single process parameters on the final product properties can be quite complicated. Usually a certain property of a product, for example the mechanical strength, has to satisfy a defined specification. In terms of quality control not only the performance of the material but also the reliability of the specified values has to be considered. The Weibull statistic gives an interesting approach to evaluate both, material's performance and reliability. Regarding the mechanical properties e.g. in terms of the stress at break σb the Weibull analysis leads to a characteristic failure constant σb,0 at which 63.2 % of the samples will break. Additionally, the Weibull modulus m can be regarded as a measure for the width of the distribution of the measuring results. High values of m represent a narrow distribution and thus a better reliability. Moreover, the Weibull modulus m is independent of the absolute value of the measuring data. Therefore, it is possible to compare samples produced under different conditions. The standard deviation and the interquartile range are often used to quantify the scatter of empirical data. It is shown within this work that the Weibull modulus m can be a more precise discriminator for the evaluation of the reliability because it is rather stable against outlaying values. As an example this study concentrates on the mechanical properties of melt spun fibres consisting of blends from polypropylenes with different molar masses produced under various process conditions. This work presents a novel chart which allows one to compare different samples on the basis of the Weibull statistics whereat the Weibull modulus m is plotted over σb,0. Defining a reference material, the m-σb,0-map can be split into quadrants, whereat each quadrant designates an improvement or worsening of material's performance and reliability with respect to the reference. An evaluation in terms of performance and reliability of great sets of data is easily applicable. It will be shown that the Weibull statistic can also be applied to Young's Modulus, the elongation at break and the tensile energy absorption.

Novel Chart for Representation of Material Performance and Reliability

Gamma interferon (IFN-γ) regulates immune defenses against viruses, intracellular pathogens, and tumors by modulating cell proliferation, migration, invasion, and vesicle trafficking processes. The large GTPase guanylate binding protein 1 (GBP-1) is among the cellular proteins that is the most abundantly induced by IFN-γ and mediates its cell biologic effects. As yet, the molecular mechanisms of action of GBP-1 remain unknown. Applying an interaction proteomics approach, we identified actin as a strong and specific binding partner of GBP-1. Furthermore, GBP-1 colocalized with actin at the subcellular level and was both necessary and sufficient for the extensive remodeling of the fibrous actin structure observed in IFN-γ-exposed cells. These effects were dependent on the oligomerization and the GTPase activity of GBP-1. Purified GBP-1 and actin bound to each other, and this interaction was sufficient to impair the formation of actin filaments in vitro, as demonstrated by atomic force microscopy, dynamic light scattering, and fluorescence-monitored polymerization. Cosedimentation and band shift analyses demonstrated that GBP-1 binds robustly to globular actin and slightly to filamentous actin. This indicated that GBP-1 may induce actin remodeling via globular actin sequestering and/or filament capping. These results establish GBP-1 as a novel member within the family of actin-remodeling proteins specifically mediating IFN-γ-dependent defense strategies.

Gamma Interferon-Induced Guanylate Binding Protein 1 Is a Novel Actin Cytoskeleton Remodeling Factor

Binary and Ternary Blends of Polypropylene Types – Influence on the Homogeneity of Biaxial‐Oriented Films

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Novel Chart for Representation of Material Performance and Reliability

Gamma Interferon-Induced Guanylate Binding Protein 1 Is a Novel Actin Cytoskeleton Remodeling Factor

Binary and Ternary Blends of Polypropylene Types – Influence on the Homogeneity of Biaxial‐Oriented Films