PDF(Pubmed)
Abstract：
Nuclear factor kappa B (NF-κB) activity is regulated by various posttranslational modifications, of which Ser276 phosphorylation of RelA/p65 is particularly impacted by reactive oxygen species (ROS). This modification is responsible for selective upregulation of a subset of NF-κB targets; however, the precise mechanism remains elusive. ROS have the ability to modify cellular molecules including DNA. One of the most common oxidation products is 8-oxo-7,8-dihydroguanine (8-oxoGua), which is repaired by the 8-oxoguanine DNA glycosylase1 (OGG1)-initiated base excision repair pathway. Recently, a new function of OGG1 has been uncovered. OGG1 binds to 8-oxoGua, facilitating the occupancy of NF-κB at promoters and enhancing transcription of pro-inflammatory cytokines and chemokines. In the present study, we demonstrated that an interaction between DNA-bound OGG1 and mitogen-and stress-activated kinase 1 is crucial for RelA/p65 Ser276 phosphorylation. ROS scavenging or OGG1 depletion/inhibition hindered the interaction between mitogen-and stress-activated kinase 1 and RelA/p65, thereby decreasing the level of phospho-Ser276 and leading to significantly lowered expression of ROS-responsive cytokine/chemokine genes, but not that of Nfkbis. Blockade of OGG1 binding to DNA also prevented promoter recruitment of RelA/p65, Pol II, and p-RNAP II in a gene-specific manner. Collectively, the data presented offer new insights into how ROS signaling dictates NF-κB phosphorylation codes and how the promoter-situated substrate-bound OGG1 is exploited by aerobic mammalian cells for timely transcriptional activation of ROS-responsive genes.
摘要：
NF-κB活性受各种翻译后修饰的调节，其中，RelA/p65的Ser276磷酸化特别受活性氧（ROS）的影响。这种修饰负责NF-κB靶标子集的选择性上调；然而，精确的机制仍然难以捉摸。ROS具有修饰细胞分子(包括DNA)的能力。最常见的氧化产物之一是8-氧代-7,8-二氢鸟嘌呤（8-氧代鸟嘌呤），由8-氧鸟嘌呤DNA糖基化酶1（OGG1）启动的碱基切除修复途径修复。最近,OGG1的新功能已被发现。OGG1与8-oxoGua结合，促进NF-κB在启动子处的占据并增强促炎细胞因子和趋化因子的转录。在本研究中,我们证明了DNA结合的OGG1与丝裂原和应激激活激酶1（MSK1）之间的相互作用对于RelA/p65Ser276磷酸化至关重要。ROS清除或OGG1耗尽/抑制阻碍了MSK1和RelA/p65之间的相互作用，从而降低了磷酸Ser276的水平，并导致ROS反应性细胞因子/趋化因子基因的表达显着降低，但不是Nfkbis的.阻断OGG1与DNA的结合也以基因特异性方式阻止了RelA/p65，PolII和p-RNAPII的启动子募集。总的来说，提供的数据提供了对ROS信号如何决定NF-κB磷酸化编码的新见解，以及需氧哺乳动物细胞如何利用启动子定位的底物结合的OGG1及时转录激活ROS反应基因。
