Innate inflammation induced by the 8-oxoguanine DNA glycosylase-1-KRAS-NF-κB pathway.
Innate inflammation induced by the 8-oxoguanine DNA glycosylase-1-KRAS-NF-κB pathway.
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由8-氧气的DNA糖基酶-1-kRAS-NF-κB途径引起的先天炎症。
DOI：
10.4049/jimmunol.1401625
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发表时间：
2014-11-01
期刊：
影响因子：
--
通讯作者：
Boldogh I
中科院分区：
文献类型：
--
作者：
Aguilera-Aguirre L;Bacsi A;Radak Z;Hazra TK;Mitra S;Sur S;Brasier AR;Ba X;Boldogh I
8-氧鸟嘌呤-DNA糖基酶-1(OGG1)是通过DNA碱基切除修复途径(OGG1-BER)修复7，8-二氢-8-氧鸟嘌呤(8-oxoG)的主要酶。8-oxoG在基因组DNA中的积累会导致遗传不稳定和致癌，并被认为是导致各种炎症和疾病过程恶化的原因之一。然而，其发病机制尚不清楚。我们认为OGG1-BER与促炎基因表达之间的机制联系是OGG1‘S鸟嘌呤核苷酸交换因子活性，该活性是在8-oxoG碱基释放后获得的，从而激活了小的GTP酶RAS。为了验证这一假设，我们利用BALB/c小鼠的呼吸道上皮细胞中表达或缺失OGG1，以及各种分子生物学方法，包括主动RAS下拉试验、报告和彗星试验、siRNA介导的基因表达缺失、定量RT-PCR和免疫印迹。我们报道，OGG1启动的氧化损伤的DNA修复是GDPKRAS GTP交换的先决条件，KRAS GTP通过MAP、PI3和MS激酶驱动的信号转导NF-→B的激活，促炎性趋化因子/细胞因子的表达，以及炎症细胞向呼吸道的募集。缺乏OGG1-BER的小鼠的免疫反应显著降低，而缺乏其他类似Nei的DNA糖基酶，即NEIL1和NEIL2，则没有显著影响。这些数据揭示了OGG1驱动的DNA BER在固有信号通路中产生炎症内源性信号中先前未知的作用。
8-Oxoguanine-DNA glycosylase-1 (OGG1) is the primary enzyme for repairing 7,8-dihydro-8-oxoguanine (8-oxoG) via the DNA base excision repair pathway (OGG1-BER). Accumulation of 8-oxoG in the genomic DNA leads to genetic instability and carcinogenesis, and is thought to contribute to the worsening of various inflammatory and disease processes. However, the disease mechanism is unknown. Here we proposed that the mechanistic link between OGG1-BER and pro-inflammatory gene expression is OGG1’s guanine nucleotide exchange factor activity, acquired after release of the 8-oxoG base and consequent activation of the small GTPase RAS. To test this hypothesis, we utilized BALB/c mice expressing or deficient in OGG1 in their airway epithelium and various molecular biological approaches, including active RAS pull-down, reporter and Comet assays, siRNA-mediated depletion of gene expression, quantitative RT-PCR, and immunoblotting. We report that the OGG1-intiated repair of oxidatively damaged DNA is a prerequisite for GDP→GTP exchange, KRAS-GTP-driven signaling via MAP-, PI3-, and MS kinases for NF-κB activation, pro-inflammatory chemokine/cytokine expression, and inflammatory cell recruitment to the airways. Mice deficient in OGG1-BER showed significantly decreased immune responses, while a lack of other Nei-like DNA glycosylases, i.e., NEIL1 and NEIL2, had no significant effect. These data unveil a previously unidentified role of OGG1-driven DNA BER in the generation of endogenous signals for inflammation in the innate signaling pathway.
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影响因子：
7.4
作者：
Hajas, Gyorgy;Bacsi, Attila;Aguilera-Aguirre, Leopoldo;Hegde, Muralidhar L.;Tapas, K. Hazra;Sur, Sanjiv;Radak, Zsolt;Ba, Xueqing;Boldogh, Istvan
通讯作者：
Boldogh, Istvan
DOI：
10.1038/nsb902
发表时间：
2003-03-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
Fromme, JC;Bruner, SD;Verdine, GL
通讯作者：
Verdine, GL
影响因子：
4.8
作者：
Hu, JP;de Souza-Pinto, NC;Bohr, VA
通讯作者：
Bohr, VA
影响因子：
14.2
作者：
Bacsi, Attila;Choudhury, Barun K.;Boldogh, Istvan
通讯作者：
Boldogh, Istvan
影响因子：
5.3
作者：
Bacsi, Attila;Chodaczek, Grzegorz;Boldogh, Istvan
通讯作者：
Boldogh, Istvan