Identification of a receptor for the orphan chemokine CXCL14

CXCL14 was first characterized in 1999 by Hromas and colleagues and called BRAK following its initial isolation from breast and kidney cells. The Cxcl14 gene encodes a 99-amino acid precursor that is processed into a 77-amino acid mature protein of ~9.4kDa in size. Expression was predominant in squamous and mucosal epithelial tissues. CXCL14 was potently upregulated by bacterial lipopolysaccharides, suggesting a role for this chemokine in proinflammatory diseases and host defense responses. While initial functions of CXCL14 suggested it was a monocyte-selective chemokine subsequent reports indicate natural killer cells, B cells, and neutrophiles may also migrate to the ligand in vitro. While there was abundant literature on CXCL14 expression and roles in leukocyte migration or angiogenesis its cognate receptor evaded definition for more than 25 years. Researchers in laboratory of Christa Muller at the University of Bonn have described a G protein coupled receptor (GPCR) abundantly expressed on mast cells, MRGPRX2, also known as MAS-related GPCR, as a receptor for the orphan chemokine CXCL14. Structural studies completed in the Muller laboratory define the molecular features needed for MRGPRX2 to activate its G-protein and arrestin signaling pathways following recognition of CXCL14. Those structure function studies were supported by their characterization of the parallel expression of CXCL14 and its receptor in the inflamed lung, rheumatoid arthritis and atopic dermatitis. Given its roles in fibroinflammatory diseases this report will be important for subsequent development of CXCL14-targeted therapies.

CXCL14 and other proinflammatory chemokines are available in the Protein Foundry catalog. 

Fig. 5 Investigation of the proposed peptide-receptor interaction site. a Cryo-EM structure of MRGPRX2 in complex Cortistatin-14 (PCKNFFWKTFSSCK with disulfide bridge: 2-13) in green color (PDB: 7S8L) superimposed by CXCL14(57-65) (STKRFIKWY) colored orange in its predicted binding pose, showing subpocket 1 and subpocket 2. The peptides that appear to be similar, FIKW and WKTF, are underlined in both sequences consisting of aromatic amino acid residues (F and W) framing two amino acid residues including a lysine (K). b Predicted binding pose of the peptide CXCL14(57-65). c Side-view of MRGPRX2 showing the transmembrane helices (TM1-TM7) and the suggested binding pocket of CXCL14(57-65), which is located near the surface of MRGPRX2 (shown in the snake plot of MRGPRX2). The amino acid residues glutamic acid (Glu1644.60), cysteine (Cys1684.64), phenylalanine (Phe170ELC2), cysteine (Cys1805.34), aspartic acid (Asp1845.38), tryptophan (Trp2436.55), leucine (Leu2476.59), and tryptophan (Trp2486.60) are shown; the amino acids in purple are polar, acidic amino acids are circled in red, and lipophilic amino acids are in green.

Communications Biology. Proinflammatory chemokine CXCL14 activates MAS-related G protein-coupled receptor MRGPRX2 and its putative mouse ortholog MRGPRB2. [Commun Biol 7, 52 (2024).]