Discovery and characterization of an endogenous CXCR4 antagonist
Onofrio Zirafi1, Kyeong-Ae Kim1, Ludger Ständker2
1Institute of Molecular Virology, University of Ulm, 89081 Ulm, Germany.
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.
Insights
Researchers discovered EPI-X4, a novel CXCR4 antagonist derived from albumin. This peptide regulates cell migration and inflammation, offering potential as a biomarker for kidney diseases.
Area of Science:
- Biochemistry
- Molecular Biology
- Immunology
Background:
- CXCL12-CXCR4 signaling is crucial for physiological processes.
- Dysregulation of this pathway is linked to cancer and inflammation.
Purpose of the Study:
- To identify novel endogenous ligands of CXCR4.
- To investigate the role of albumin fragments in CXCR4 regulation.
Main Methods:
- Screening of a blood-derived peptide library against CXCR4-tropic HIV-1 strains.
- Identification and characterization of a 16 amino acid albumin fragment (EPI-X4).
- Assessment of EPI-X4's biological activities in vitro and in vivo.
Main Results:
- A novel, highly specific CXCR4 antagonist, EPI-X4, was identified from serum albumin.
- EPI-X4 antagonizes CXCL12-induced tumor cell migration and suppresses inflammatory responses in mice.
- EPI-X4 is evolutionarily conserved and generated by pH-regulated proteases.
Conclusions:
- EPI-X4 is a key endogenous regulator of CXCR4 signaling.
- Proteolysis of abundant proteins offers a new paradigm for chemokine receptor regulation.
- EPI-X4 may serve as a biomarker for inflammatory kidney diseases.
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