SFPQ 通过与 miRNA 诱导的沉默复合物相互作用，参与调节砷诱导的氧化应激。,Environmental Pollution

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SFPQ 通过与 miRNA 诱导的沉默复合物相互作用，参与调节砷诱导的氧化应激。
Environmental Pollution ( IF 7.6 ) Pub Date : 2020-02-10 , DOI: 10.1016/j.envpol.2020.114160
Ping Guo ₁ , Shen Chen ₁ , Daochuan Li ₁ , Jinmiao Zhang ₁ , Jiao Luo ₂ , Aihua Zhang ₃ , Dianke Yu ₂ , Michael S Bloom ₄ , Liping Chen ₁ , Wen Chen ₁

Affiliation

砷暴露有助于人类疾病的发展。砷主要通过引发氧化应激而产生多种器官毒性。然而，氧化应激的信号通路尚不清楚。我们之前发现，剪接因子 SFPQ 的表达与砷暴露人群中的尿砷浓度呈正相关，表明 SFPQ 具有氧化应激调节作用。为了验证这一假设，我们在用 NaAsO2 处理的人肝细胞 (L02) 中建立了氧化应激的细胞模型。随着 NaAsO2 处理，活性氧 (ROS) 合成显示出时间和剂量依赖性增加。SFPQ 抑制导致 ROS 生成减少 36%-53%，导致由 8-OHdG、彗星尾矩和微核分析确定的细胞损伤增强。特别，SFPQ 缺陷减弱了氧化酶基因 DUOX1、DUOX2、NCF2 和 NOX2 的表达。基于荧光的 RNA 电泳迁移率变化测定 (FREMSA) 和双荧光素酶报告系统显示 miR-92b-5p 靶向 DUOX2 mRNA 降解。RNA 免疫沉淀分析显示 SFPQ 与 miRNA 诱导的沉默复合物 (miRISC) 的 miR-92b-5p 之间存在相互作用。值得注意的是，NaAsO2 处理减少了 SFPQ 和 miR92b-5p 之间的相互作用，伴随着 miR-92b-5p 和 DUOX2 3'-UTR 之间的结合降低。然而，SFPQ 缺陷抑制了 miR-92b-5p 从 DUOX2 3'-UTR 的解离，表明 miR-92b-5p 调节了 SFPQ 依赖性 DUOX2 表达。总之，我们揭示了 SFPQ 通过与 miRISC 相互作用来响应砷诱导的氧化应激。

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SFPQ is involved in regulating arsenic-induced oxidative stress by interacting with the miRNA-induced silencing complexes.

Arsenic exposure contributed to the development of human diseases. Arsenic exerted multiple organ toxicities mainly by triggering oxidative stress. However, the signaling pathway underlying oxidative stress is unclear. We previously found that the expression of SFPQ, a splicing factor, was positively associated with urinary arsenic concentration in an arsenic-exposed population, suggesting an oxidative stress regulatory role for SFPQ. To test this hypothesis, we established cell models of oxidative stress in human hepatocyte cells (L02) treated with NaAsO2. Reactive oxygen species (ROS) synthesis displayed a time- and dose-dependent increase with NaAsO2 treatment. SFPQ suppression resulted in a 36%-53% decrease in ROS generation, leading to enhanced cellular damage determined by 8-OHdG, comet tail moment, and micronucleus analysis. Particularly, SFPQ deficiency attenuated expression of the oxidase genes DUOX1, DUOX2, NCF2, and NOX2. A fluorescent-based RNA electrophoretic mobility shift assay (FREMSA) and dual-luciferase reporter system revealed that miR-92b-5p targeted DUOX2 mRNA degradation. An RNA immunoprecipitation assay showed an interaction between SFPQ and miR-92b-5p of the miRNA-induced silencing complex (miRISC). Notably, NaAsO2 treatment diminished the interaction between SFPQ and miR92b-5p, accompanied by decreased binding between miR-92b-5p and 3'-UTR of DUOX2. However, SFPQ deficiency suppressed the dissociation of miR-92b-5p from 3'-UTR of DUOX2, indicating that miR-92b-5p regulated the SFPQ-dependent DUOX2 expression. Taken together, we reveal that SFPQ responds to arsenic-induced oxidative stress by interacting with the miRISC. These findings offer new insight into the potential role of SFPQ in regulating cellular stress response.

更新日期：2020-02-10

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