Institute of Pathology Case Western Reserve University and Cardiovascular Research Institute, Department of Medicine, Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, United States.
Cardiovascular Research of Medicine, Case Western Reserve University, Cleveland, OH, United States.
Front Immunol. 2024 Feb 9;14:1290684. doi: 10.3389/fimmu.2023.1290684. eCollection 2023.
The transcription factor Kruppel-like factor 4 (KLF4) regulates the expression of immunosuppressive and anti-thrombotic proteins. Despite its importance in maintaining homeostasis, the signals that control its expression and the mechanism of its transactivation remain unclarified. CD55 [aka decay accelerating factor (DAF)], now known to be a regulator of T and B cell responses, biases between pro- and anti-inflammatory processes by controlling autocrine C3a and C5a receptor (C3ar1/C5ar1) signaling in cells. The similarity in CD55's and KLF4's regulatory effects prompted analyses of their functional relationship. In vascular endothelial cells (ECs), CD55 upregulation accompanied KLF4 expression via a p-CREB and CREB Binding Protein (CBP) mechanism. In both ECs and macrophages, CD55 expression was essential for KLF4's downregulation of pro-inflammatory/pro-coagulant proteins and upregulation of homeostatic proteins. Mechanistic studies showed that upregulation of KLF4 upregulated CD55. The upregulated CD55 in turn enabled the recruitment of p-CREB and CBP to KLF4 needed for its transcription. Activation of adenylyl cyclase resulting from repression of autocrine C3ar1/C5ar1 signaling by upregulated CD55 concurrently led to p-CREB and CBP recruitment to KLF4-regulated genes, thereby conferring KLF4's transactivation. Accordingly, silencing CD55 in statin-treated HUVEC disabled CBP transfer from the E-selectin to the eNOS promoter. Importantly, silencing CD55 downregulated KLF4's expression. It did the same in untreated HUVEC transitioning from KLF4 growth to KLF4 contact inhibition. KLF4's and CD55's function in ECs and macrophages thus are linked via a novel mechanism of gene transactivation. Because the two proteins are co-expressed in many cell types, CD55's activity may be broadly tied to KLF4's immunosuppressive and antithrombotic activities.
转录因子 Kruppel 样因子 4（KLF4）调节免疫抑制和抗血栓蛋白的表达。尽管它在维持体内平衡方面很重要，但控制其表达的信号及其转录激活的机制仍不清楚。CD55[又名衰变加速因子（DAF）]，现在已知是 T 和 B 细胞反应的调节剂，通过控制细胞内的自分泌 C3a 和 C5a 受体（C3ar1/C5ar1）信号，在促炎和抗炎过程之间产生偏向。CD55 和 KLF4 的调节作用相似，促使人们分析它们的功能关系。在血管内皮细胞（ECs）中，CD55 的上调伴随着 KLF4 的表达，这是通过 p-CREB 和 CREB 结合蛋白（CBP）机制实现的。在 ECs 和巨噬细胞中，CD55 的表达对于 KLF4 下调促炎/促凝蛋白和上调稳态蛋白是必不可少的。机制研究表明，KLF4 的上调上调了 CD55 的表达。上调的 CD55 反过来又使 p-CREB 和 CBP 募集到 KLF4 转录所需的位置。上调的 CD55 通过抑制自分泌 C3ar1/C5ar1 信号来抑制腺苷酸环化酶的激活，同时导致 p-CREB 和 CBP 募集到 KLF4 调节的基因，从而赋予 KLF4 的转录激活。因此，在他汀类药物处理的 HUVEC 中沉默 CD55 会使 CBP 从 E-选择蛋白转移到 eNOS 启动子的能力丧失。重要的是，沉默 CD55 下调了 KLF4 的表达。在未处理的 HUVEC 中，从 KLF4 生长到 KLF4 接触抑制的过程中也是如此。因此，KLF4 和 CD55 在 ECs 和巨噬细胞中的功能通过一种新的基因转录激活机制联系在一起。由于这两种蛋白在许多细胞类型中都有共同表达，因此 CD55 的活性可能与 KLF4 的免疫抑制和抗血栓作用广泛相关。
