Down-regulation of monocyte tissue factor mediated by tissue factor pathway inhibitor and the low density lipoprotein receptor-related protein
Down-regulation of monocyte tissue factor mediated by tissue factor pathway inhibitor and the low density lipoprotein receptor-related protein
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DOI：
10.1074/jbc.274.8.4962
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发表时间：
1999-02-19
影响因子：
4.8
通讯作者：
Morrissey, JH
中科院分区：
文献类型：
--
作者：
Hamik, A;Setiadi, H;Morrissey, JH
细菌脂多糖等炎症介质诱导单核细胞表达组织因子 (TF)，组织因子是一种细胞表面蛋白，可触发止血和血栓性疾病中的凝血级联反应。 TF 的生理配体是丝氨酸蛋白酶、因子 VIIa (FVIIa)，所产生的双分子酶 TF/FVIIa 可以被组织因子途径抑制剂 (TFPI) 可逆地抑制。在 FVIIa 和 TFPI 存在的情况下培养单核细胞，可通过缩短其半衰期来下调 TF 表达。为了发挥这种作用，FVIIa必须能够结合TF和TFPI，并且TFPI必须含有与其他细胞表面受体结合所需的C端结构域，包括低密度脂蛋白受体相关蛋白（LRP），FVIIa加TFPI对TF的下调被39-kDa受体相关蛋白消除，该蛋白阻止所有已知配体与LRP的结合。此外，用FVIIa加TFPI治疗导致单核细胞 TF 与 α-适应素（网格蛋白包被的凹坑的一种成分）共定位。因此，除了可逆地抑制 TF/FVIIa 催化活性外，TFPI 还通过 LRP 依赖性内化和降解介导单核细胞中细胞表面 TF 的永久下调。这代表了一种不寻常的受体内化机制，需要一个细胞表面受体（TF）与第二个细胞表面受体（LRP）进行配体依赖性桥接，后者能够进行网格蛋白介导的内化。
Inflammatory mediators like bacterial lipopolysaccharide induce monocytes to express tissue factor (TF), the cell-surface protein that triggers the blood clotting cascade in hemostasis and thrombotic disease. The physiologic ligand for TF is the serine protease, factor VIIa (FVIIa), and the resulting bimolecular enzyme, TF/FVIIa, can be reversibly inhibited by tissue factor pathway inhibitor (TFPI), Culturing monocytic cells in the presence of both FVIIa and TFPI caused down-regulation of TF expression via reducing its half-life. To exert this effect, FVIIa had to be competent to bind both TF and TFPI, and TFPI had to contain the C-terminal domain required for binding to other cell-surface receptors, including the low density lipoprotein receptor-related protein (LRP), TF down-regulation by FVIIa plus TFPI was abrogated by the 39-kDa receptor-associated protein, which blocks binding of all known ligands to LRP, Furthermore, treatment with FVIIa plus TFPI caused monocyte TF to colocalize with alpha-adaptin, a component of clathrin-coated pits. Thus, in addition to reversibly inhibiting TF/FVIIa catalytic activity, TFPI also mediates the permanent down-regulation of cell-surface TF in monocytic cells via LRP-dependent internalization and degradation. This represents an unusual mechanism for receptor internalization, requiring ligand-dependent bridging of one cell-surface receptor (TF) to a second cell-surface receptor (LRP), the latter being capable of clathrin-mediated internalization.