Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4.
Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4.
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DOI：
10.1096/fj.201700013r
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发表时间：
2017-07
期刊：
影响因子：
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通讯作者：
Moser B
中科院分区：
文献类型：
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作者：
Collins PJ;McCully ML;Martínez-Muñoz L;Santiago C;Wheeldon J;Caucheteux S;Thelen S;Cecchinato V;Laufer JM;Purvanov V;Monneau YR;Lortat-Jacob H;Legler DF;Uguccioni M;Thelen M;Piguet V;Mellado M;Moser B
趋化因子受体CXC趋化因子受体4(CXCR4)是CXC趋化因子配体12(CXCL12)的选择性受体，广泛表达于血液和组织细胞中，在胚胎发育和造血过程中起重要作用。CXCL14是一种动态平衡趋化因子，具有未知的受体选择性，在外周组织中优先表达。在这里，我们证明了CXCL14与CXCL12在诱导原代人类淋巴样细胞和表达CXCR4的细胞系中的趋化因子反应方面具有协同作用。将非活性浓度的CXCL12与100-300 nM的CXCL14相结合，产生的趋化反应超过了单独使用CXCL12所获得的最大反应。CXCL14不能激活表达CXCR4的细胞(即不能启动趋化和钙动员，也不能通过ERK1/2和小的GTPase rac1进行信号传递)；但CXCL14与CXCR4高亲和力结合，诱导细胞表面CXCR4的重新分布，并使HIV-1感染增加3倍。我们推测CXCL14是CXCR4的正变构调节剂，可以增强CXCR4配体的效力。我们的发现提供了新的见解，将为针对包括癌症、自身免疫和艾滋病毒在内的一系列疾病的CXCR4的新疗法的开发提供信息。-Collins，P.J.，McCully，M.L.，Martínez-Muñoz，L.，Santiago，C.，Wheeldon，J.，Caucheteux，S.，Thelen，S.，CecChinto，V.，Laufer，J.M.，Purvanov，V.，Monneau，Y.R.，Lortat-Jacob，H.，Legler，D.F.，Uuguccioni，M.，Thelen，M.，Piguet，V.，Mellado，M.，Moser，J.上皮细胞趋化因子CXCL14通过CXCR4的变构调节与CXCL12协同作用。
The chemokine receptor, CXC chemokine receptor 4 (CXCR4), is selective for CXC chemokine ligand 12 (CXCL12), is broadly expressed in blood and tissue cells, and is essential during embryogenesis and hematopoiesis. CXCL14 is a homeostatic chemokine with unknown receptor selectivity and preferential expression in peripheral tissues. Here, we demonstrate that CXCL14 synergized with CXCL12 in the induction of chemokine responses in primary human lymphoid cells and cell lines that express CXCR4. Combining subactive concentrations of CXCL12 with 100–300 nM CXCL14 resulted in chemotaxis responses that exceeded maximal responses that were obtained with CXCL12 alone. CXCL14 did not activate CXCR4-expressing cells (i.e., failed to trigger chemotaxis and Ca2+ mobilization, as well as signaling via ERK1/2 and the small GTPase Rac1); however, CXCL14 bound to CXCR4 with high affinity, induced redistribution of cell-surface CXCR4, and enhanced HIV-1 infection by >3-fold. We postulate that CXCL14 is a positive allosteric modulator of CXCR4 that enhances the potency of CXCR4 ligands. Our findings provide new insights that will inform the development of novel therapeutics that target CXCR4 in a range of diseases, including cancer, autoimmunity, and HIV.—Collins, P. J., McCully, M. L., Martínez-Muñoz, L., Santiago, C., Wheeldon, J., Caucheteux, S., Thelen, S., Cecchinato, V., Laufer, J. M., Purvanov, V., Monneau, Y. R., Lortat-Jacob, H., Legler, D. F., Uguccioni, M., Thelen, M., Piguet, V., Mellado, M., Moser, B. Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4.