Discovery and Characterization of an Endogenous CXCR4 Antagonist

CXCL12-CXCR4 signaling controls multiple physiological and its dysregulation is associated cancers and inflammatory diseases. To as-yet-unknown endogenous ligands of 4, we screened a blood-derived peptide library inhibitors of CXCR4-tropic HIV-1 strains. approach identified a 16 amino acid fragment serum albumin as an effective and highly specific 4 antagonist. The endogenous peptide, termed -X4, is evolutionarily conserved and generated the highly abundant albumin precursor by -regulated proteases. EPI-X4 forms an unusual -like structure and antagonizes CXCL12-induced cell migration, mobilizes stem cells, suppresses inflammatory responses in mice. , the peptide is abundant in the urine patients with inflammatory kidney diseases and serve as a biomarker. Our results identify EPIX4 a key regulator of CXCR4 signaling and introduce of an abundant precursor protein an alternative concept for chemokine receptor .