Heparan Sulfate Glycosaminoglycan Binding Sites in CXCL12 Isoforms Differentially Promote Cellular Adhesion and Migration
The chemokine family of immune modulators have pleiotropic functions explained in part by ligand–receptor redundancy, influence of glycosaminoglycans and atypical chemokine receptors (ACKR) on ligand gradients, alterations in gene expression, or discrete pharmacologic signaling. CXCL12 and its receptors CXCR4 and ACKR3 have a high degree of fidelity and nearly ubiquitous expression across cells and tissues. Given this conservation, functional selectivity downstream of CXCR4 is mediated by CXCL12 six distinct isoforms (α, β, γ, δ, ε, θ).
CXCL12 isoforms (α, β, and γ) arise by alternative splicing. CXCL12γ expression is restrained to endothelial vessels and relative to ubiquitously expressed CXCL12α, CXCL12γ differs from the major isoform CXCL12α by a long carboxy-terminal domain highly enriched in basic amino acids, encompassing 5 canonical heparan sulfate glycosaminoglycan binding motifs, compared to the single heparan sulfate binding site in CXCL12α. Recent work in Blood Advances by Lantermans and colleagues demonstrate that the heparan sulfate binding sites in the CXCL12γ carboxy terminus promotes stronger leukocyte adhesion to vascular endothelial cells than CXCL12α. This increased cell adhesion was mediated without CXCL12γ-mediated internalization of CXCR4.
The authors then went on to show that retention of CXCR4 on the surface of leukocytes facilitates the ability of those cells to respond to a subsequent chemical gradient of the CXCL12α isoform. These data illustrate how structural changes in the CXCL12α and CXCL12γ isoforms provide different functional outcomes that work collaboratively to control the trafficking of immune cells.
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Blood Advances 2025 Feb 19:bloodadvances.2024014396. Online ahead of print. Presentation of CXCL12? by heparan sulfate proteoglycans activates CXCR4 without desensitization in B cells. Lantermans, Ma, Kuil, de Rooij, Bergkamp, van der Meer, van Buul, Smit, Kersten, Spaargaren, and Pals. PMID: 39969206