Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA.
Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA; Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
Cell Signal. 2017 Nov;39:18-31. doi: 10.1016/j.cellsig.2017.07.019. Epub 2017 Jul 25.
The human apurinic/apyrimidinic endonuclease 1 (APE1) is a pleiotropic nuclear protein with roles in DNA base excision repair pathway as well as in regulation of transcription. Recently, the presence of extracellular plasma APE1 was reported in endotoxemic rats. However, the biological significance and the extracellular function of APE1 remain unclear. In this study, we found that monocytes secrete APE1 upon inflammatory challenges. Challenging the monocytic cells with extracellular APE1 resulted in the increased expression and secretion of the pro-inflammatory cytokine IL-6. Additionally, the extracellular APE1 treatment activated the transcription factor NF-κB, followed by its increased occupancy at the IL-6 promoter, resulting in the induction of IL-6 expression. APE1-induced IL-6 further served to elicit autocrine and paracrine cellular responses. Moreover, the extracellular IL-6 promoted the secretion of APE1, thus indicating a functional feedforward loop in this pathway. Furthermore, we show that APE1 is secreted through extracellular vesicles formation via endosomal sorting complex required for transport (ESCRT)-dependent pathway. Together, our study demonstrates a novel role of extracellular APE1 in IL-6-dependent cellular responses.
人类脱嘌呤/脱嘧啶核酸内切酶 1（APE1）是一种多功能核蛋白，在 DNA 碱基切除修复途径以及转录调控中发挥作用。最近，在内毒素血症大鼠中报道了细胞外血浆 APE1 的存在。然而，APE1 的生物学意义和细胞外功能仍不清楚。在这项研究中，我们发现单核细胞在炎症挑战下会分泌 APE1。用细胞外 APE1 挑战单核细胞会导致促炎细胞因子 IL-6 的表达和分泌增加。此外，细胞外 APE1 处理激活了转录因子 NF-κB，随后其在 IL-6 启动子上的占有率增加，导致 IL-6 的诱导表达。APE1 诱导的 IL-6 进一步引发自分泌和旁分泌细胞反应。此外，细胞外 IL-6 促进了 APE1 的分泌，因此表明该途径中存在功能反馈环。此外，我们表明 APE1 通过内体分选复合物所需的运输（ESCRT）依赖性途径通过细胞外囊泡形成而分泌。总之，我们的研究表明细胞外 APE1 在 IL-6 依赖性细胞反应中发挥新的作用。
