The unique structural and functional features of CXCL12

Abstract

The CXC chemokine CXCL12 is an important factor in physiological and pathological processes, including embryogenesis, hematopoiesis, angiogenesis and inflammation, because it activates and/or induces migration of hematopoietic progenitor and stem cells, endothelial cells and most leukocytes. Therefore, CXCL12 activity is tightly regulated at multiple levels. CXCL12 has the unique property of existing in six splice variants in humans, each having a specific tissue distribution and in vivo activity. Controlled splice variant transcription and mRNA stability determine the CXCL12 expression profile. CXCL12 fulfills its functions in homeostatic and pathological conditions by interacting with its receptors CXC chemokine receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) and by binding to glycosaminoglycans (GAGs) in tissues and on the endothelium to allow a proper presentation to passing leukocytes. Homodimerizaton and heterodimerization of CXCL12 and its receptors can alter their signaling activity, as exemplified by the synergy between CXCL12 and other chemokines in leukocyte migration assays. Receptor binding may also initiate CXCL12 internalization and its subsequent removal from the environment. Furthermore, CXCL12 activity is regulated by posttranslational modifications. Proteolytic removal of NH₂- or COOH-terminal amino acids, citrullination of arginine residues by peptidyl arginine deiminases or nitration of tyrosine residues reduce CXCL12 activity. This review summarizes the interactions of CXCL12 with the cellular environment and discusses the different levels of CXCL12 activity regulation.

Keywords: ACKR3; CXCL12; CXCR4; chemokine; regulation.

Figure 1

Posttranslational modifications of CXCL12α. (a) The amino-acid sequence (using the one-letter code) of CXCL12α is shown with the indicated GAG and receptor-binding domains. The enzymes responsible for NH₂- and COOH-terminal truncation are indicated, and the cleaved amino acids are shown in red. Arg residues susceptible to citrullination by PAD activity are shown in yellow, and Tyr residues that may be nitrated are shown in green. (b) A 3D model of CXCL12α shows the localization of the potentially removed (red), citrullinated (yellow) and nitrated (green) amino acids. These amino acids are indicated with their three-letter code on the 3D model drawn from PDB accession code 2 kec.

Figure 2

Signal transduction pathways activated by CXCL12. Stimulation of both CXCR4 and ACKR3 triggers a signaling cascade involving many second messengers. The primary pathways are depicted with green arrows, whereas inhibitory interactions are shown with a red line. Dashed lines represent signaling pathways that are without consensus in the literature. ERK1/2, extracellular signal-regulated kinase 1/2; GRK, G protein-coupled receptor kinase; IP₃, inositol 3-phosphate; JAK2/3, Janus kinase 2/3; NF-κB, nuclear factor kappa-light-chain enhancer of activated B cells; PI3K, phosphatidylinositol-3-kinase; PLC, phospholipase C; STAT, signal transducer and activator of transcription.

Figure 3

Levels of CXCL12 activity regulation. CXCL12 activity is controlled at multiple levels, starting with (a) controlled transcription and mRNA splicing of CXCL12 variants and (b) subsequent regulation of mRNA stability by microRNA (miRNA). After translation, CXCL12 and its receptor may be posttranslationally modified by several enzymes or chemical agents (c). On the endothelium, interaction of CXCL12 with GAGs is necessary for its immobilization on blood vessels and its presentation to passing leukocytes (d). This GAG interaction favors CXCL12 homo- and heterodimerization (e) and protects CXCL12 from posttranslational modifications. The seven-transmembrane domain receptors CXCR4 and ACKR3 are activated by CXCL12 and are able to form homo- or heterodimers among each other or with other chemokine receptors (f). ACKR3 internalizes CXCL12 and alters its gradient (g), whereas synergy between CXCL12 and other chemokines increases the response of target cells (h).