Interaction of Serum-Derived and Internalized C3 With DNA in Human B Cells-A Potential Involvement in Regulation of Gene Transcription
Interaction of Serum-Derived and Internalized C3 With DNA in Human B Cells-A Potential Involvement in Regulation of Gene Transcription
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DOI：
10.3389/fimmu.2019.00493
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发表时间：
2019-03-19
影响因子：
7.3
通讯作者：
Blom, Anna M.
中科院分区：
文献类型：
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作者：
Kremlitzka, Mariann;Nowacka, Alicja A.;Blom, Anna M.
除了作为天然免疫的血清效应系统的经典作用外，越来越多的证据表明，补体在细胞内具有一系列成分，不仅提供免疫防御，而且还具有维持细胞内平衡的功能。虽然已经在B细胞中检测到补体蛋白，主要是中央成分C3，但它们的确切功能和来源在很大程度上仍未被探索。在这项研究中，我们研究了细胞内C3在人B细胞中的表达和来源，以及它在B细胞内稳态中的作用。我们的数据提供了证据，证明C3在人类B细胞中的内源性表达非常低，根据最近的报道，细胞内C3的主要来源是血清。有趣的是，我们发现血清来源的C3和纯化的C3都能够进入活B细胞的核，这表明它可能参与了基因转录的调节。EL ISA、凝胶漂移分析、共聚焦显微镜和染色质免疫沉淀实验证明，C3和C3a与核DNA结合强烈，在相互作用的基因中，存在着影响淋巴细胞发育和分化的关键因素。C3与组蛋白的强相互作用及其诱导染色质重排的潜在能力表明，C3/C3a可能通过染色质重塑来调节DNA转录。我们的数据揭示了C3在免疫细胞动态平衡中的一个新的、迄今未被描述的作用，它进一步扩展了补体如何连接天然免疫和获得性免疫并调节细胞的基本过程。
Beside its classical role as a serum effector system of innate immunity, evidence is accumulating that complement has an intracellular repertoire of components that provides not only immune defense, but also functions to maintain cellular homeostasis. While complement proteins, mainly the central component C3, have been detected in B cells, their exact function and source remain largely unexplored. In this study, we investigated the expression and origin of intracellular C3 in human B cells together with its role in B cell homeostasis. Our data provide evidence that endogenous expression of C3 is very low in human B cells and, in accordance with the recent publication, the main origin of intracellular C3 is the serum. Interestingly, we found that both serum-derived and purified C3 are able to enter the nucleus of viable B cells, suggesting its potential involvement in regulation of gene transcription. ELISA, gel shift assay, confocal microscopy, and chromatin immunoprecipitation proved that C3 and C3a strongly bind to nuclear DNA, and among the interacting genes there are key factors of lymphocyte development and differentiation. The strong interaction of C3 with histone proteins and its potential ability to induce chromatin rearrangement suggest that C3/C3a might regulate DNA transcription via chromatin remodeling. Our data reveal a novel, hitherto undescribed role of C3 in immune cell homeostasis, which further extends the repertoire how complement links innate and adaptive immunity and regulates basic processes of the cells.