Cell Reports (May 2015)
Discovery and Characterization of an Endogenous CXCR4 Antagonist
- 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,
- Jan Münch
Affiliations
- Onofrio Zirafi
- Institute of Molecular Virology, University of Ulm, 89081 Ulm, Germany
- Kyeong-Ae Kim
- Institute of Molecular Virology, University of Ulm, 89081 Ulm, Germany
- Ludger Ständker
- Institute of Molecular Virology, University of Ulm, 89081 Ulm, Germany
- Katharina B. Mohr
- Institute of Molecular Virology, University of Ulm, 89081 Ulm, Germany
- Daniel Sauter
- Institute of Molecular Virology, University of Ulm, 89081 Ulm, Germany
- Anke Heigele
- Institute of Molecular Virology, University of Ulm, 89081 Ulm, Germany
- Silvia F. Kluge
- Institute of Molecular Virology, University of Ulm, 89081 Ulm, Germany
- Eliza Wiercinska
- German Red Cross Blood Service Baden-Württemberg-Hessen and Institute for Transfusion Medicine and Immunohaematology, Goethe University, 60528 Frankfurt, Germany
- Doreen Chudziak
- German Red Cross Blood Service Baden-Württemberg-Hessen and Institute for Transfusion Medicine and Immunohaematology, Goethe University, 60528 Frankfurt, Germany
- Rudolf Richter
- German Red Cross Blood Service Baden-Württemberg-Hessen and Institute for Transfusion Medicine and Immunohaematology, Goethe University, 60528 Frankfurt, Germany
- Barbara Moepps
- Institute of Pharmacology and Toxicology, University of Ulm, 89081 Ulm, Germany
- Peter Gierschik
- Institute of Pharmacology and Toxicology, University of Ulm, 89081 Ulm, Germany
- Virag Vas
- Department of Dermatology and Allergic Diseases, University of Ulm, 89081 Ulm, Germany
- Hartmut Geiger
- Department of Dermatology and Allergic Diseases, University of Ulm, 89081 Ulm, Germany
- Markus Lamla
- Institute of Organic Chemistry III, University of Ulm, 89081 Ulm, Germany
- Tanja Weil
- Institute of Organic Chemistry III, University of Ulm, 89081 Ulm, Germany
- Timo Burster
- Department of Neurosurgery, University of Ulm, 89081 Ulm, Germany
- Andreas Zgraja
- PHARIS Biotec GmbH, 30625 Hannover, Germany
- Francois Daubeuf
- UMR7200, Therapeutic Innovation Lab, CNRS-University of Strasbourg, Faculty of Pharmacy, and LabEx Medalis, 67401 Illkirch, France
- Nelly Frossard
- UMR7200, Therapeutic Innovation Lab, CNRS-University of Strasbourg, Faculty of Pharmacy, and LabEx Medalis, 67401 Illkirch, France
- Muriel Hachet-Haas
- UMR7242, Biotechnology and Cellular Signaling, School of Biotechnology of Strasbourg, 67412 Illkirch, France
- Fabian Heunisch
- Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal-Potsdam, Germany
- Christoph Reichetzeder
- Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal-Potsdam, Germany
- Jean-Luc Galzi
- UMR7242, Biotechnology and Cellular Signaling, School of Biotechnology of Strasbourg, 67412 Illkirch, France
- Javier Pérez-Castells
- Department of Chemistry, University San Pablo-CEU, 280040 Madrid, Spain
- Angeles Canales-Mayordomo
- Department of Physico-Chemical Biology, Centro de Investigaciones Biológicas, 28040 Madrid, Spain
- Jesus Jiménez-Barbero
- Department of Physico-Chemical Biology, Centro de Investigaciones Biológicas, 28040 Madrid, Spain
- Guillermo Giménez-Gallego
- Department of Physico-Chemical Biology, Centro de Investigaciones Biológicas, 28040 Madrid, Spain
- Marion Schneider
- Experimental Anesthesiology Section, University Hospital Ulm, 89081 Ulm, Germany
- James Shorter
- Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
- Amalio Telenti
- J. Craig Venter Institute, La Jolla, CA 92037, USA
- Berthold Hocher
- Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal-Potsdam, Germany
- Wolf-Georg Forssmann
- Institute of Molecular Virology, University of Ulm, 89081 Ulm, Germany
- Halvard Bonig
- German Red Cross Blood Service Baden-Württemberg-Hessen and Institute for Transfusion Medicine and Immunohaematology, Goethe University, 60528 Frankfurt, Germany
- Frank Kirchhoff
- Institute of Molecular Virology, University of Ulm, 89081 Ulm, Germany
- Jan Münch
- Institute of Molecular Virology, University of Ulm, 89081 Ulm, Germany
- DOI
- https://doi.org/10.1016/j.celrep.2015.03.061
- Journal volume & issue
-
Vol. 11,
no. 5
pp. 737 – 747
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.
