Department of Medicine, Imperial College London, London, United Kingdom.
Mol Med. 2012 May 9;18(1):636-46. doi: 10.2119/molmed.2011.00321.
Protein A (SpA) of Staphylococcus aureus is known to target the paratope of immunoglobulins expressing V(H)3 genes, and to delete marginal zone B cells and B-1a in vivo. We have discovered that SpA endows S. aureus with the potential to subvert B-cell trafficking in the host. We found that SpA, whose Fc-binding site has been inactivated, binds essentially to naïve B cells and induces a long-lasting decrease in CXCR4 expression and in B-cell chemotaxis to CXCL12. Competition experiments indicated that SpA does not interfere with binding of CXCR4 ligands and does not directly bind to CXCR4. This conclusion is strongly supported by the inability of SpA to modulate clathrin-mediated CXCR4 internalization, which contrasts with the potent effect of anti-immunoglobin M (IgM) antibodies. Microscopy and biochemical experiments confirmed that SpA binds to the surface IgM/IgD complex and induces its clathrin-dependent internalization. Concomitantly, the SpA-induced signaling leads to protein kinase C-dependent CXCR4 downmodulation, suggesting that SpA impairs the recycling of CXCR4, a postclathrin process that leads to either degradation into lysozomes or de novo expression at the cell surface. In addition to providing novel insight into disruption of B-cell trafficking by an infectious agent, our findings may have therapeutic implications. Because CXCR4 has been associated with cancer metastasis and with certain autoimmune diseases, SpA behaves as an evolutionary tailored highly specific, chemokine receptor inhibitor that may have value in addition to conventional cytotoxic therapy in patients with various malignancies and immune-mediated diseases.
金黄色葡萄球菌的蛋白 A（SpA）已知靶向表达 V(H)3 基因的免疫球蛋白的变区，并且在体内删除边缘区 B 细胞和 B-1a。我们发现 SpA 赋予金黄色葡萄球菌潜在能力，从而在宿主中颠覆 B 细胞的迁移。我们发现，其 Fc 结合位点已失活的 SpA 主要结合幼稚 B 细胞，并诱导 CXCR4 表达和 B 细胞对 CXCL12 的趋化性的持久降低。竞争实验表明，SpA 不干扰 CXCR4 配体的结合，也不直接结合 CXCR4。该结论得到以下实验的强烈支持：SpA 不能调节网格蛋白介导的 CXCR4 内化，这与抗免疫球蛋白 M（IgM）抗体的强烈作用形成对比。显微镜和生化实验证实 SpA 结合表面 IgM/IgD 复合物并诱导其网格蛋白依赖性内化。同时，SpA 诱导的信号导致蛋白激酶 C 依赖性 CXCR4 下调，表明 SpA 损害了 CXCR4 的再循环，这是网格蛋白内化后的过程，导致 CXCR4 降解到溶酶体中或在细胞表面重新表达。除了为感染因子破坏 B 细胞迁移提供新的见解外，我们的发现可能具有治疗意义。由于 CXCR4 与癌症转移和某些自身免疫性疾病有关，因此 SpA 作为一种进化定制的高度特异性趋化因子受体抑制剂，除了传统的细胞毒性疗法外，在患有各种恶性肿瘤和免疫介导性疾病的患者中可能具有价值。
