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2. Compound heterozygous variants in OTULIN are associated with fulminant atypical late‐onset ORAS

Author

Julia Zinngrebe, Barbara Moepps, Thomas Monecke, Peter Gierschik, Ferdinand Schlichtig, Thomas F E Barth, Gudrun Strauß, Elena Boldrin, Carsten Posovszky, Ansgar Schulz, Ortraud Beringer, Eva Rieser, Eva‐Maria Jacobsen, Myriam Ricarda Lorenz, Klaus Schwarz, Ulrich Pannicke, Henning Walczak, Dierk Niessing, Catharina Schuetz, Pamela Fischer‐Posovszky, and Klaus‐Michael Debatin

Subjects
autoinflammation, linear ubiquitin, LUBAC, ORAS, OTULIN, Medicine (General), R5-920, Genetics, QH426-470
Abstract

Abstract Autoinflammatory diseases are a heterogenous group of disorders defined by fever and systemic inflammation suggesting involvement of genes regulating innate immune responses. Patients with homozygous loss‐of‐function variants in the OTU‐deubiquitinase OTULIN suffer from neonatal‐onset OTULIN‐related autoinflammatory syndrome (ORAS) characterized by fever, panniculitis, diarrhea, and arthritis. Here, we describe an atypical form of ORAS with distinct clinical manifestation of the disease caused by two new compound heterozygous variants (c.258G>A (p.M86I)/c.500G>C (p.W167S)) in the OTULIN gene in a 7‐year‐old affected by a life‐threatening autoinflammatory episode with sterile abscess formation. On the molecular level, we find binding of OTULIN to linear ubiquitin to be compromised by both variants; however, protein stability and catalytic activity is most affected by OTULIN variant p.W167S. These molecular changes together lead to increased levels of linear ubiquitin linkages in patient‐derived cells triggering the disease. Our data indicate that the spectrum of ORAS patients is more diverse than previously thought and, thus, supposedly asymptomatic individuals might also be affected. Based on our results, we propose to subdivide the ORAS into classical and atypical entities.

Published
2022
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5. Genetic Factors of the Disease Course After Sepsis: Rare Deleterious Variants Are Predictive

Author

Stefan Taudien, Ludwig Lausser, Evangelos J. Giamarellos-Bourboulis, Christoph Sponholz, Franziska Schöneweck, Marius Felder, Lyn-Rouven Schirra, Florian Schmid, Charalambos Gogos, Susann Groth, Britt-Sabina Petersen, Andre Franke, Wolfgang Lieb, Klaus Huse, Peter F. Zipfel, Oliver Kurzai, Barbara Moepps, Peter Gierschik, Michael Bauer, André Scherag, Hans A. Kestler, and Matthias Platzer

Subjects
Sepsis, Exome, Rare single nucleotide variation, Population stratification, Classification, Semantic set covering machine, Medicine, Medicine (General), R5-920
Abstract

Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection. For its clinical course, host genetic factors are important and rare genomic variants are suspected to contribute. We sequenced the exomes of 59 Greek and 15 German patients with bacterial sepsis divided into two groups with extremely different disease courses. Variant analysis was focusing on rare deleterious single nucleotide variants (SNVs). We identified significant differences in the number of rare deleterious SNVs per patient between the ethnic groups. Classification experiments based on the data of the Greek patients allowed discrimination between the disease courses with estimated sensitivity and specificity > 75%. By application of the trained model to the German patients we observed comparable discriminatory properties despite lower population-specific rare SNV load. Furthermore, rare SNVs in genes of cell signaling and innate immunity related pathways were identified as classifiers discriminating between the sepsis courses. Sepsis patients with favorable disease course after sepsis, even in the case of unfavorable preconditions, seem to be affected more often by rare deleterious SNVs in cell signaling and innate immunity related pathways, suggesting a protective role of impairments in these processes against a poor disease course.

Published
2016
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6. Discovery and Characterization of an Endogenous CXCR4 Antagonist

Author

Onofrio Zirafi, Kyeong-Ae Kim, Ludger Ständker, Katharina B. Mohr, Daniel Sauter, Anke Heigele, Silvia F. Kluge, Eliza Wiercinska, Doreen Chudziak, Rudolf Richter, Barbara Moepps, Peter Gierschik, Virag Vas, Hartmut Geiger, Markus Lamla, Tanja Weil, Timo Burster, Andreas Zgraja, Francois Daubeuf, Nelly Frossard, Muriel Hachet-Haas, Fabian Heunisch, Christoph Reichetzeder, Jean-Luc Galzi, Javier Pérez-Castells, Angeles Canales-Mayordomo, Jesus Jiménez-Barbero, Guillermo Giménez-Gallego, Marion Schneider, James Shorter, Amalio Telenti, Berthold Hocher, Wolf-Georg Forssmann, Halvard Bonig, Frank Kirchhoff, and Jan Münch

Subjects
Biology (General), QH301-705.5
Abstract

CXCL12-CXCR4 signaling controls multiple physiological processes and its dysregulation is associated with cancers and inflammatory diseases. To discover as-yet-unknown endogenous ligands of CXCR4, we screened a blood-derived peptide library for inhibitors of CXCR4-tropic HIV-1 strains. This approach identified a 16 amino acid fragment of serum albumin as an effective and highly specific CXCR4 antagonist. The endogenous peptide, termed EPI-X4, is evolutionarily conserved and generated from the highly abundant albumin precursor by pH-regulated proteases. EPI-X4 forms an unusual lasso-like structure and antagonizes CXCL12-induced tumor cell migration, mobilizes stem cells, and suppresses inflammatory responses in mice. Furthermore, the peptide is abundant in the urine of patients with inflammatory kidney diseases and may serve as a biomarker. Our results identify EPI-X4 as a key regulator of CXCR4 signaling and introduce proteolysis of an abundant precursor protein as an alternative concept for chemokine receptor regulation.

Published
2015
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15. Royal academy of medicine in ireland section of biomedical sciences: Proceedings of winter meeting 1995

Author

Galligan, E., Al-Assar, O., McIntyre, I. A., McKeown, S. R., Hollywood, M. A., Thornbury, K. D., McHale, N. G., Keenan, A. K., Gierschik, P., Nelson, A. A., McKenna, P. G., Barnett, Y. A., Curran, A. K., O’Halloran, K. D., Bradford, A., O’Haloran, K. D., Curran, A. K., Bradford, A., Kent, A., Keenan, A. K., Redrobe, J. P., Kelly, J. P., Leonard, B. E., Chambers, P. L., Ryan, P. M., Kelly, J. P., Leonard, B. E., Chambers, P. L., Redmond, A. M., Kelly, J. P., Leonard, B. E., McNamara, M. G., Kelly, J. P., Leonard, B. E., McShane, A. J., Tobin, E., Smith, T., Fox, G. B., Kennedy, N., Regan, C. M., O’Farrell, F. J., Hannigan, B. M., Barnett, Y. A., Walsh, I. K., Johnston, S. R., McKelvey-Martin, V. J., McKeown, S. R., McAleer, J. J. A., O’Halloran, K. D., Curran, A. K., Bradford, A., Curran, A. K., O’Halloran, K. D., Bradford, A., O’Regan, R. G., Kelly, J. P., Leonard, B. E., Mullen, A. M., Earley, B., Leonard, B. E., O’Neill, J., O’Connor, J. J., Moynagh, P., O’Neill, L. A. J., Kelly, J. A., Keenan, A. K., McHale, N. G., Gierschik, P., Browne, I., Gavin, K., Docherty, J. R., Smith, K., Gavin, K., Docherty, J. R., Cawley, T., Docherty, J. R., Geraghty, J., Osborne, H., Hyland, P. L., McKinney, M. W., McKenna, P. G., Barnett, Y. A., McKeown, S. R., Hejmadi, M. V., McAleer, J. J. A., Patterson, L. H., Sweeney, M., McLoughlin, P., O’Donnell, M. D., McGeeney, K. F., and Cottell, D. C.

Published
1995
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20. Royal academy of medicine in Ireland section of biomedical sciences: Proceedings of Winter Meeting held 4th January 1994 at the Veterinary College, University College Dublin

Author

Doolan, C. M., Keenan, A. K., Costello, C. M., McQuaid, K., O’Connor, C. M., Fitzgerald, M. X., Southey, A., Ryan, P., Kelly, J., Leonard, B. E., Grace, D., Fee, J. P. H., Milligan, K. R., Brazil, D., Clyne, C., Camps, M., McHale, N. G., Keenan, A. K, Gierschik, P., Caldwell, M., O’Neill, M., Earley, B., Thornton, F., Martin, F., O’Connnell, A., Benicourt, C., O’Donnell, J. M., Banyasz, T., Kovacs, T., Campion, D. P., Leek, B. F., Smith, K. M., Docherty, J. R., McNamara, M., Kelly, J. P., McGarvey, C., O’Donnell, J., Nsimba, S. E. D., Kelly, B. E., MacSweeney, C., Redrobe, J. P., Browne, I., Gavin, K., Thomas, G., Docherty, J. R, Ryan, M., Burke, W., McDonnell, T., Clyne, C. D., Healy, E., Hunt, A., Ryan, M. P., Tashani, O. A., Curran, A. K., O’Halloran, K. D., Bradford, A., O’Halloran, K. D, Ryan, J. P., Rousseau, J. P., Kearns, P. O., Quinn, T. M., Kevin, L. G., Doran, M., Tansey, D., Boylan, J., McShane, A. J., Wen, Y., Feely, J., Lowe, A. S., Baxter, G. D., Walsh, D. M., McDowell, B., Allen, J. M., McDowell, B. C., Allen, I. M., Niveditha, Y., O’Donovan, D. J., O’Neill, J., Powell, D., Kernan, R. P., Foster, N. E. L., and Orr, A.

Published
1994
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23. Evaluation of vecabrutinib as a model for noncovalent BTK/ITK inhibition for treatment of chronic lymphocytic leukemia

Author

Jebaraj, Billy Michael Chelliah, Müller, Annika, Dheenadayalan, Rashmi Priyadharshini, Endres, Sascha, Roessner, Philipp M., Seyfried, Felix, Walliser, Claudia, Wist, Martin, Qi, Jialei, Tausch, Eugen, Mertens, Daniel, Fox, Judith A., Debatin, Klaus-Michael, Meyer, Lüder Hinrich, Taverna, Pietro, Seiffert, Martina, Gierschik, Peter, and Stilgenbauer, Stephan

Abstract

Covalent Bruton tyrosine kinase (BTK) inhibitors, such as ibrutinib, have proven to be highly beneficial in the treatment of chronic lymphocytic leukemia (CLL). Interestingly, the off-target inhibition of IL-2-inducible T-cell kinase (ITK) by ibrutinib may also play a role in modulating the tumor microenvironment, potentially enhancing the treatment benefit. However, resistance to covalently binding BTK inhibitors can develop as the result of a mutation in cysteine 481 of BTK (C481S), which prevents irreversible binding of the drugs. In the present study we performed preclinical characterization of vecabrutinib, a next-generation noncovalent BTK inhibitor that has ITK-inhibitory properties similar to those of ibrutinib. Unlike ibrutinib and other covalent BTK inhibitors, vecabrutinib showed retention of the inhibitory effect on C481S BTK mutants in vitro, similar to that of wild-type BTK. In the murine Eμ-TCL1 adoptive transfer model, vecabrutinib reduced tumor burden and significantly improved survival. Vecabrutinib treatment led to a decrease in CD8+effector and memory T-cell populations, whereas the naive populations were increased. Of importance, vecabrutinib treatment significantly reduced the frequency of regulatory CD4+T cells in vivo. Unlike ibrutinib, vecabrutinib treatment showed minimal adverse impact on the activation and proliferation of isolated T cells. Lastly, combination treatment with vecabrutinib and venetoclax augmented treatment efficacy, significantly improved survival, and led to favorable reprogramming of the microenvironment in the murine Eμ-TCL1 model. Thus, noncovalent BTK/ITK inhibitors, such as vecabrutinib, may be efficacious in C481S BTK mutant CLL while preserving the T-cell immunomodulatory function of ibrutinib.

Published
2022
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29. Genetic Factors of the Disease Course After Sepsis: Rare Deleterious Variants Are Predictive

Author

Taudien, S. Lausser, L. Giamarellos-Bourboulis, E.J. Sponholz, C. Schöneweck, F. Felder, M. Schirra, L.-R. Schmid, F. Gogos, C. Groth, S. Petersen, B.-S. Franke, A. Lieb, W. Huse, K. Zipfel, P.F. Kurzai, O. Moepps, B. Gierschik, P. Bauer, M. Scherag, A. Kestler, H.A. Platzer, M.

Abstract

Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection. For its clinical course, host genetic factors are important and rare genomic variants are suspected to contribute. We sequenced the exomes of 59 Greek and 15 German patients with bacterial sepsis divided into two groups with extremely different disease courses. Variant analysis was focusing on rare deleterious single nucleotide variants (SNVs). We identified significant differences in the number of rare deleterious SNVs per patient between the ethnic groups. Classification experiments based on the data of the Greek patients allowed discrimination between the disease courses with estimated sensitivity and specificity > 75%. By application of the trained model to the German patients we observed comparable discriminatory properties despite lower population-specific rare SNV load. Furthermore, rare SNVs in genes of cell signaling and innate immunity related pathways were identified as classifiers discriminating between the sepsis courses. Sepsis patients with favorable disease course after sepsis, even in the case of unfavorable preconditions, seem to be affected more often by rare deleterious SNVs in cell signaling and innate immunity related pathways, suggesting a protective role of impairments in these processes against a poor disease course. © 2016 The Authors

Published
2016

31. The Rac-RhoGDI complex and the structural basis for the regulation of Rho proteins by RhoGDI

Author

Scheffzek, K., Stephan, I., Jensen, O., Illenberger, D., and Gierschik, P.

Subjects
Models, Molecular, rho GTP-Binding Proteins, Binding Sites, Protein Conformation, Hydrolysis, Cell Membrane, Molecular Sequence Data, Proteins, Crystallography, X-Ray, Lipid Metabolism, Guanosine Diphosphate, rac GTP-Binding Proteins, Amino Acid Sequence, Guanosine Triphosphate, Guanine Nucleotide Dissociation Inhibitors
Abstract

Udgivelsesdato: 2000-Feb Rho family-specific guanine nucleotide dissociation inhibitors (RhoGDIs) decrease the rate of nucleotide dissociation and release Rho proteins such as RhoA, Rac and Cdc42 from membranes, forming tight complexes that shuttle between cytosol and membrane compartments. We have solved the crystal structure of a complex between the RhoGDI homolog LyGDI and GDP-bound Rac2, which are abundant in leukocytes, representing the cytosolic, resting pool of Rho species to be activated by extracellular signals. The N-terminal domain of LyGDI (LyN), which has been reported to be flexible in isolated RhoGDIs, becomes ordered upon complex formation and contributes more than 60% to the interface area. The structure is consistent with the C-terminus of Rac2 binding to a hydrophobic cavity previously proposed as isoprenyl binding site. An inner segment of LyN forms a helical hairpin that contacts mainly the switch regions of Rac2. The architecture of the complex interface suggests a mechanism for the inhibition of guanine nucleotide dissociation that is based on the stabilization of the magnesium (Mg2+) ion in the nucleotide binding pocket.

Published
2000

32. TGFbeta1 represses proliferation of pancreatic carcinoma cells which correlates with Smad4-independent inhibition of ERK activation

Author

Giehl, K., Seidel, B., Gierschik, P., Adler, G., Menke, A., and Publica

Subjects
pancreatic cancer
Abstract

Transforming growth factor beta (TGFbeta) is a tumor suppressor acting as inhibitor of cell cycle progression of epithelial cells. We show that treatment of the pancreatic, carcinoma cell lines PANC-1 and BxPC-3 with TGFbeta1 inhibits both growth factor-induced activation of the extracellular signal-regulated kinase 2 (ERK2) and translocation of the kinase to the nucleus. TGFbeta1 causes a concentration-dependent reduction of cell proliferation in both cell lines. By measuring ERK activation, we can show that TGFbeta1 is able to repress ERK activation induced by mitogenic stimuli such as EGF. This inhibitory effect of TGFbeta1 is not mediated by suppression of Ras or c-Raf-1 activation, but mediated by TGFbeta1-induced activation of a serine-threonine phosphatase, as demonstrated by inhibition of phosphatases by treatment with okadaic acid. Results obtained in the Smad4-deficient pancreatic carcinoma cell line BxPC-3, demonstrate that TGFbeta1-induced growth inhibition is mediated by a Smad4-independent prevention of ERK2 activation. In contrast to the effects of TGFbeta1 on epithelial cells, mesenchymal NIH3T3 fibroblasts exhibit elevated ERK2 activation and increased cell proliferation in response to TGFbeta1 treatment. Smad4-independent phosphatase-mediated inhibition of mitogen-activated ERK2 represents a novel effector pathway contributing to suppression of epithelial pancreatic carcinoma cell proliferation by TGFbeta1, in addition to the well-known Smad-induced tumor suppressor activity of TGFbeta.

Published
2000

38. Severe Early-Onset Obesity Due to Bioinactive Leptin Caused by a p.N103K Mutation in the Leptin Gene

Author

Wabitsch, Martin, Funcke, Jan-Bernd, von Schnurbein, Julia, Denzer, Friederike, Lahr, Georgia, Mazen, Inas, El-Gammal, Mona, Denzer, Christian, Moss, Anja, Debatin, Klaus-Michael, Gierschik, Peter, Mistry, Vanisha, Keogh, Julia M., Farooqi, I. Sadaf, Moepps, Barbara, and Fischer-Posovszky, Pamela

Abstract

Context:Congenital leptin deficiency is a very rare cause of severe early-onset obesity. We recently characterized a mutation in the leptin gene (p.D100Y), which was associated with detectable leptin levels and bioinactivity of the hormone.Case Description:We now describe two siblings, a 9-year-old girl and a 6-year-old boy with severe early-onset obesity and hyperphagia, both homozygous for a c.309C>A substitution in the leptin gene leading to a p.N103K amino acid exchange in the protein and detectable circulating levels of leptin. In vitro experiments in a heterologous cell system demonstrated that the mutated protein was biologically inactive. Treatment with sc recombinant human leptin led to rapid improvement of eating behavior and weight loss.Conclusions:Sequencing of the leptin gene may need to be considered in hyperphagic, severely obese children with detectable levels of circulating leptin.

Published
2015
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39. Discovery and Characterization of an Endogenous CXCR4 Antagonist

Author

Zirafi, Onofrio, Kim, Kyeong-Ae, Ständker, Ludger, Mohr, Katharina B., Sauter, Daniel, Heigele, Anke, Kluge, Silvia F., Wiercinska, Eliza, Chudziak, Doreen, Richter, Rudolf, Moepps, Barbara, Gierschik, Peter, Vas, Virag, Geiger, Hartmut, Lamla, Markus, Weil, Tanja, Burster, Timo, Zgraja, Andreas, Daubeuf, Francois, Frossard, Nelly, Hachet-Haas, Muriel, Heunisch, Fabian, Reichetzeder, Christoph, Galzi, Jean-Luc, Pérez-Castells, Javier, Canales-Mayordomo, Angeles, Jiménez-Barbero, Jesus, Giménez-Gallego, Guillermo, Schneider, Marion, Shorter, James, Telenti, Amalio, Hocher, Berthold, Forssmann, Wolf-Georg, Bonig, Halvard, Kirchhoff, Frank, and Münch, Jan

Abstract

CXCL12-CXCR4 signaling controls multiple physiological processes and its dysregulation is associated with cancers and inflammatory diseases. To discover as-yet-unknown endogenous ligands of CXCR4, we screened a blood-derived peptide library for inhibitors of CXCR4-tropic HIV-1 strains. This approach identified a 16 amino acid fragment of serum albumin as an effective and highly specific CXCR4 antagonist. The endogenous peptide, termed EPI-X4, is evolutionarily conserved and generated from the highly abundant albumin precursor by pH-regulated proteases. EPI-X4 forms an unusual lasso-like structure and antagonizes CXCL12-induced tumor cell migration, mobilizes stem cells, and suppresses inflammatory responses in mice. Furthermore, the peptide is abundant in the urine of patients with inflammatory kidney diseases and may serve as a biomarker. Our results identify EPI-X4 as a key regulator of CXCR4 signaling and introduce proteolysis of an abundant precursor protein as an alternative concept for chemokine receptor regulation.

Published
2015
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