Auto-oxidation and oligomerization of protein S on the apoptotic cell surface is required for met tyrosine kinase-mediated phagocytosis of apoptotic cells
Auto-oxidation and oligomerization of protein S on the apoptotic cell surface is required for met tyrosine kinase-mediated phagocytosis of apoptotic cells
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DOI：
10.4049/jimmunol.180.4.2522
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发表时间：
2008-02-15
影响因子：
4.4
通讯作者：
Shacter, Emily
中科院分区：
文献类型：
--
作者：
Uehara, Hiroshi;Shacter, Emily
凋亡细胞的迅速吞噬可防止对死亡细胞的炎症和自身免疫反应。我们之前已经证明血液抗凝因子蛋白S刺激人单核细胞来源的巨噬细胞吞噬凋亡的人B淋巴瘤细胞。在这项研究中，我们发现蛋白S必须首先经过氧化活化才能刺激吞噬作用。人蛋白S与凋亡细胞或磷脂酰丝氨酸多层囊泡结合可促进蛋白S中Cys残基的自氧化，产生共价二硫键二聚体和低聚物，优先结合并激活巨噬细胞上的人Mer酪氨酸激酶（MerTK）受体。当二硫化物介导的寡聚被阻止，或者当中性抗体阻断MerTK时，蛋白S的原吞噬活性被消除。蛋白S的寡聚不依赖于磷脂氧化。这些数据表明，含有磷脂酰丝氨酸的膜作为蛋白-蛋白- S相互作用的支架，由此产生的自氧化和寡聚化是蛋白S的前吞噬活性所必需的。通过这种方式，凋亡细胞促进巨噬细胞对其自身的摄取。蛋白S对氧化修饰的需求可以解释为什么这种丰富的血液蛋白在循环单核细胞和组织巨噬细胞中不能组成性地激活MerTK。
Prompt phagocytosis of apoptotic cells prevents inflammatory and autoimmune responses to dying cells. We have previously shown that the blood anticoagulant factor protein S stimulates phagocytosis of apoptotic human B lymphoma cells by human monocyte-derived macrophages. In this study, we show that protein S must first undergo oxidative activation to stimulate phagocytosis. Binding of human protein S to apoptotic cells or to phosphatidylserine multilamellar vesicles promotes auto-oxidation of Cys residues in protein S, resulting in covalent, disulfide-linked dimers and oligomers that preferentially bind to and activate the human Mer tyrosine kinase (MerTK) receptor on the macrophages. The prophagocytic activity of protein S is eliminated when disulfide-mediated oligomerization is prevented, or when MerTK is blocked with neutralizing Abs. Protein S oligomerization is independent of phospholipid oxidation. The data suggest that membranes containing phosphatidylserine serve as a scaffold for protein S-protein S interactions and that the resulting auto-oxidation and oligomerization is required for the prophagocytic activity of protein S. In this way, apoptotic cells facilitate their own uptake by macrophages. The requirement for oxidative modification of protein S can explain why this abundant blood protein does not constitutively activate MerTK in circulating monocytes and tissue macrophages.