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 EPIX4
as a key regulator of CXCR4 signaling and introduce
proteolysis of an abundant precursor protein
as an alternative concept for chemokine receptor
regulation
