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Discovery and characterization of an endogenous CXCR4 antagonist

  • 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.

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Author:Onofrio Zirafi, Kyeong-Ae Kim, Ludger Ständker, Katharina B. Mohr, Daniel Sauter, Anke Heigele, Silvia F. Kluge, Eliza WiercinskaORCiDGND, 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-Björn BönigORCiDGND, Frank Kirchhoff, Jan Münch
URN:urn:nbn:de:hebis:30:3-534370
DOI:https://doi.org/10.1016/j.celrep.2015.03.061
ISSN:2211-1247
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/25921529
Parent Title (English):Cell Reports
Publisher:Cell Press
Place of publication:Maryland Heights, MO
Document Type:Article
Language:English
Date of Publication (online):2015/04/23
Date of first Publication:2015/04/23
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/06/17
Volume:11
Issue:5
Page Number:34
First Page:737
Last Page:747
HeBIS-PPN:467081611
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell - Keine Bearbeitung 4.0