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.
Institute of Molecular Virology, University of Ulm, 89081 Ulm, Germany.
Onofrio
O
Zirafi
Institute of Molecular Virology, University of Ulm, 89081 Ulm, Germany.
Kyeong-Ae
KA
Kim
Institute of Molecular Virology, University of Ulm, 89081 Ulm, Germany; Ulm Peptide Pharmaceuticals, University of Ulm, 89081 Ulm, Germany; PHARIS Biotec GmbH, 30625 Hannover, Germany.
Ludger
L
Ständker
Institute of Molecular Virology, University of Ulm, 89081 Ulm, Germany.
Katharina B
KB
Mohr
Institute of Molecular Virology, University of Ulm, 89081 Ulm, Germany.
Daniel
D
Sauter
Institute of Molecular Virology, University of Ulm, 89081 Ulm, Germany.
Anke
A
Heigele
Institute of Molecular Virology, University of Ulm, 89081 Ulm, Germany.
Silvia F
SF
Kluge
German Red Cross Blood Service Baden-Württemberg-Hessen and Institute for Transfusion Medicine and Immunohaematology, Goethe University, 60528 Frankfurt, Germany.
Eliza
E
Wiercinska
German Red Cross Blood Service Baden-Württemberg-Hessen and Institute for Transfusion Medicine and Immunohaematology, Goethe University, 60528 Frankfurt, Germany.
Doreen
D
Chudziak
German Red Cross Blood Service Baden-Württemberg-Hessen and Institute for Transfusion Medicine and Immunohaematology, Goethe University, 60528 Frankfurt, Germany; Department of Internal Medicine, Clinic of Immunology, Hannover Medical School, 30625 Hannover, Germany.
Rudolf
R
Richter
Institute of Pharmacology and Toxicology, University of Ulm, 89081 Ulm, Germany.
Barbara
B
Moepps
Institute of Pharmacology and Toxicology, University of Ulm, 89081 Ulm, Germany.
Peter
P
Gierschik
Department of Dermatology and Allergic Diseases, University of Ulm, 89081 Ulm, Germany.
Virag
V
Vas
Department of Dermatology and Allergic Diseases, University of Ulm, 89081 Ulm, Germany.
Hartmut
H
Geiger
Institute of Organic Chemistry III, University of Ulm, 89081 Ulm, Germany.
Markus
M
Lamla
Institute of Organic Chemistry III, University of Ulm, 89081 Ulm, Germany.
Tanja
T
Weil
Department of Neurosurgery, University of Ulm, 89081 Ulm, Germany.
Timo
T
Burster
PHARIS Biotec GmbH, 30625 Hannover, Germany.
Andreas
A
Zgraja
UMR7200, Therapeutic Innovation Lab, CNRS-University of Strasbourg, Faculty of Pharmacy, and LabEx Medalis, 67401 Illkirch, France.
Francois
F
Daubeuf
UMR7200, Therapeutic Innovation Lab, CNRS-University of Strasbourg, Faculty of Pharmacy, and LabEx Medalis, 67401 Illkirch, France.
Nelly
N
Frossard
UMR7242, Biotechnology and Cellular Signaling, School of Biotechnology of Strasbourg, 67412 Illkirch, France.
Muriel
M
Hachet-Haas
Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal-Potsdam, Germany.
Fabian
F
Heunisch
Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal-Potsdam, Germany.
Christoph
C
Reichetzeder
UMR7242, Biotechnology and Cellular Signaling, School of Biotechnology of Strasbourg, 67412 Illkirch, France.
Jean-Luc
JL
Galzi
Department of Chemistry, University San Pablo-CEU, 280040 Madrid, Spain.
Javier
J
Pérez-Castells
Department of Physico-Chemical Biology, Centro de Investigaciones Biológicas, 28040 Madrid, Spain.
Angeles
A
Canales-Mayordomo
Department of Physico-Chemical Biology, Centro de Investigaciones Biológicas, 28040 Madrid, Spain.
Jesus
J
Jiménez-Barbero
Department of Physico-Chemical Biology, Centro de Investigaciones Biológicas, 28040 Madrid, Spain.
Guillermo
G
Giménez-Gallego
Experimental Anesthesiology Section, University Hospital Ulm, 89081 Ulm, Germany.
Marion
M
Schneider
Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
James
J
Shorter
J. Craig Venter Institute, La Jolla, CA 92037, USA.
Amalio
A
Telenti
Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal-Potsdam, Germany.
Berthold
B
Hocher
Institute of Molecular Virology, University of Ulm, 89081 Ulm, Germany; PHARIS Biotec GmbH, 30625 Hannover, Germany; Department of Internal Medicine, Clinic of Immunology, Hannover Medical School, 30625 Hannover, Germany.
Wolf-Georg
WG
Forssmann
German Red Cross Blood Service Baden-Württemberg-Hessen and Institute for Transfusion Medicine and Immunohaematology, Goethe University, 60528 Frankfurt, Germany.
Halvard
H
Bonig
Institute of Molecular Virology, University of Ulm, 89081 Ulm, Germany; Ulm Peptide Pharmaceuticals, University of Ulm, 89081 Ulm, Germany.
Frank
F
Kirchhoff
Institute of Molecular Virology, University of Ulm, 89081 Ulm, Germany; Ulm Peptide Pharmaceuticals, University of Ulm, 89081 Ulm, Germany. Electronic address: jan.muench@uni-ulm.de.
Jan
J
Münch
D000595:Amino Acid Sequence; D000818:Animals; D015415:Biomarkers / Q000652:urine; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D057809:HEK293 Cells; D015497:HIV-1 / Q000502:physiology; D006207:Half-Life; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000378:metabolism / Q000473:pathology; D016415:Sequence Alignment; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D053586:Virus Internalization / Q000187:drug effects
D015415:Biomarkers; C000622392:EPI-X4 peptide, human; D010446:Peptide Fragments; D019151:Peptide Library; D010455:Peptides; D019718:Receptors, CXCR4; D012709:Serum Albumin