C1q binds phosphatidylserine and likely acts as a multiligand-bridging molecule in apoptotic cell recognition
C1q binds phosphatidylserine and likely acts as a multiligand-bridging molecule in apoptotic cell recognition
复制标题
DOI：
10.4049/jimmunol.180.4.2329
复制
发表时间：
2008-02-15
影响因子：
4.4
通讯作者：
Frachet, Philippe
中科院分区：
文献类型：
--
作者：
Paidassi, Helena;Tacnet-Delorme, Pascale;Frachet, Philippe
有效的凋亡细胞清除对于维持组织稳态和控制吞噬细胞介导的免疫反应至关重要。我们对凋亡细胞表面产生“吃我”信号的分子知之甚少。C1q是补体C1复合体的识别单位，也能感知自身结构的改变，是免疫耐受的主要参与者。通过UV-B处理导致HeLa细胞凋亡，并使用各种细胞和分子方法来研究C1q识别的靶标的性质。利用表面等离子体共振，C1q结合被证明发生在细胞凋亡的早期阶段，并涉及对细胞膜成分的识别。通过膜联蛋白V标记测量，C1q结合和磷脂酰丝氨酸（PS）暴露同时进行，膜联蛋白V以剂量依赖的方式抑制Clq结合。共沉淀、表面等离子体共振和x射线晶体学分析表明，C1q通过其球状结构域与PS的磷酸丝氨酸基团之间的多重相互作用，特异性和强烈地识别PS （K-D = 3.7-7 x 10(-8) M）。共聚焦显微镜显示，大部分C1q分子分布在膜斑块中，并与PS共定位。和C1q-PS的相互作用发生在凋亡的早期阶段，在新组织的膜斑块中。鉴于其多功能识别特性，这些数据表明C1q具有独特的能力，可以感知不同的标记物，这些标记物共同提供强烈的“吃我”信号，从而允许有效的凋亡细胞清除。
Efficient apoptotic cell clearance is critical for maintenance of tissue homeostasis, and to control the immune responses mediated by phagocytes. Little is known about the molecules that contribute "eat me" signals on the apoptotic cell surface. C1q, the recognition unit of the C1 complex of complement, also senses altered structures from self and is a major actor of immune tolerance. HeLa cells were rendered apoptotic by UV-B treatment and a variety of cellular and molecular approaches were used to investigate the nature of the target(s) recognized by C1q. Using surface plasmon resonance, C1q binding was shown to occur at early stages of apoptosis and to involve recognition of a cell membrane component. C1q binding and phosphatidylserine (PS) exposure, as measured by annexin V labeling, proceeded concomitantly, and annexin V inhibited Clq binding in a dose-dependent manner. As shown by cosedimentation, surface plasmon resonance, and x-ray crystallographic analyses, C1q recognized PS specifically and avidly (K-D = 3.7-7 x 10(-8) M), through multiple interactions between its globular domain and the phosphoserine group of PS. Confocal microscopy revealed that the majority of the C1q molecules were distributed in membrane patches where they colocalized with PS. In summary, PS is one of the C1q ligands on apoptotic cells, and C1q-PS interaction takes place at early stages of apoptosis, in newly organized membrane patches. Given its versatile recognition properties, these data suggest that C1q has the unique ability to sense different markers which collectively would provide strong eat me signals, thereby allowing efficient apoptotic cell removal.