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Role of CXC chemokine receptor type 4 as a lactoferrin receptor

机译：CXC趋化因子受体类型4作为乳铁蛋白受体的作用

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摘要

Lactoferrin exerts its biological activities by interacting with receptors on target cells, including LDL receptor-related protein-1 (LRP-1/CD91), intelectin-1 (omentin-1), and Toll-like receptor 4 (TLR4). However, the effects mediated by these receptors are not sufficient to fully explain the many functions of lactoferrin. C-X-C-motif cytokine receptor 4 (CXCR4) is a ubiquitously expressed G-protein coupled receptor for stromal cell-derived factor-1 (SDF-1/CXCL12). Lactoferrin was found to be as capable as SDF-1 in blocking infection by an HIV variant that uses CXCR4 as a co-receptor (X4-tropic HIV), suggesting that lactoferrin interacts with CXCR4. We addressed whether CXCR4 acts as a lactoferrin receptor using HaCaT human keratinocytes and Caco-2 human intestinal cells. We found that bovine lactoferrin interacted with CXCR4-containing lipoparticles, and that this interaction was not antagonized by SDF-1. In addition, activation of Akt in response to lactoferrin was abrogated by AMD3100, a small molecule inhibitor of CXCR4, or by a CXCR4-neutralizing antibody, suggesting that CXCR4 functions as a lactoferrin receptor able to mediate activation of the PI3K–Akt signaling pathway. Lactoferrin stimulation mimicked many aspects of SDF-1-induced CXCR4 activity, including receptor dimerization, tyrosine phosphorylation, and ubiquitination. Cycloheximide chase assays indicated that turnover of CXCR4 was accelerated in response to lactoferrin. These results indicate that CXCR4 is a potent lactoferrin receptor that mediates lactoferrin-induced activation of Akt signaling.
机译：乳铁蛋白通过与靶细胞的受体相互作用，包括LDL受体相关蛋白-1（LRP-1 / CD91），intelectIN-1（Opentin-1）和Toll样受体4（TLR4）来施加生物活性。然而，这些受体介导的效果不足以充分解释乳铁蛋白的许多功能。 C-X-C-MOTIF细胞因子受体4（CXCR4）是用于基质细胞衍生因子-1（SDF-1 / CXCL12）的普遍意表达的G-蛋白偶联受体。发现乳铁蛋白在通过使用CXCR4作为共同受体（X4-热带艾滋病毒）的HIV变体阻断感染，表明乳铁蛋白与CXCR4相互作用。我们解决了CXCR4是否用HACAT人角蛋白细胞和Caco-2人肠细胞用作乳铁蛋白受体。我们发现牛乳铁蛋白与含CXCR4的脂肪颗粒相互作用，并且该相互作用未被SDF-1拮抗。此外，通过AMD3100，CXCR4的小分子抑制剂或通过CXCR4中和抗体消除AKT响应于乳铁蛋白的AKT活化，表明CXCR4用作能够介导PI3K-AKT信号通路的活化的乳蛋白受体。乳铁蛋白刺激模仿SDF-1诱导的CXCR4活性的许多方面，包括受体二聚化，酪氨酸磷酸化和泛素化。环己酰亚胺追踪测定表明，响应于乳铁蛋白加速CXCR4的成交量。这些结果表明CXCR4是介导乳铁蛋白诱导的AKT信号传导激活的有效乳蛋白受体。

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