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Long noncoding RNA MAGI2-AS3 regulates the H2O2 level and cell senescence via HSPA8
Redox Biology ( IF 11.4 ) Pub Date : 2022-06-30 , DOI: 10.1016/j.redox.2022.102383
Yingmin Zhang 1 , Xinhua Qiao 2 , Lihui Liu 3 , Wensheng Han 1 , Qinghua Liu 3 , Yuanyuan Wang 1 , Ting Xie 1 , Yiheng Tang 4 , Tiepeng Wang 2 , Jiao Meng 2 , Aojun Ye 1 , Shunmin He 4 , Runsheng Chen 4 , Chang Chen 1
Affiliation  

The redox homeostasis system regulates many biological processes, intracellular antioxidant production and redox signaling. However, long noncoding RNAs (lncRNAs) involved in redox regulation have rarely been reported. Herein, we reported that downregulation of MAGI2-AS3 decreased the superoxide level in Human fibroblasts (Fbs), a replicative aging model, as detected by the fluorescent probes dihydroethidium (DHE) and MitoSOX™ Red. RNA pulldown combined with mass spectrometry showed that HSPA8 is a novel interacting protein of MAGI2-AS3, which was further confirmed by photoactivatable ribonucleoside–enhanced crosslinking and immunoprecipitation (PAR-CLIP). Downregulation of MAGI2-AS3 decreased the hydrogen peroxide (H2O2) content by stabilizing the HSPA8 protein level via inhibiting the protesome degradation of HSPA8. Further evidence showed that MAGI2-AS3 interacted with the C-terminal domain (CTD) of HSPA8. Downregulation of MAGI2-AS3 delayed cell senescence, while this antiaging effect was abolished by HSPA8 knockdown. The underlying molecular mechanism by which MAGI2-AS3 knockdown inhibited cell senescence was mediated via suppression of the ROS/MAP2K6/p38 signaling pathway. Taken together, these findings revealed that downregulation of lncRNA MAGI2-AS3 decreased the H2O2 content and delayed cell senescence by stabilizing the HSPA8 protein level, identifying a potential antiaging application.



中文翻译:

长链非编码 RNA MAGI2-AS3 通过 HSPA8 调节 H2O2 水平和细胞衰老

氧化还原稳态系统调节许多生物过程、细胞内抗氧化剂的产生和氧化还原信号。然而,很少报道参与氧化还原调节的长链非编码 RNA (lncRNA)。在此,我们报道了 MAGI2-AS3 的下调降低了人类成纤维细胞 (Fbs) 中的超氧化物水平,这是一种复制性衰老模型,由荧光探针二氢乙锭 (DHE) 和 MitoSOX™ Red 检测到。RNA pulldown 结合质谱表明 HSPA8 是一种新型的 MAGI2-AS3 相互作用蛋白,光活化核糖核苷增强的交联和免疫沉淀 (PAR-CLIP) 进一步证实了这一点。MAGI2-AS3 的下调降低了过氧化氢 (H 2 O 2) 通过抑制 HSPA8 的蛋白酶体降解来稳定 HSPA8 蛋白水平。进一步的证据表明,MAGI2-AS3 与 HSPA8 的 C 末端结构域 (CTD) 相互作用。MAGI2-AS3 的下调延迟了细胞衰老,而这种抗衰老作用被 HSPA8 敲低消除了。MAGI2-AS3 敲低抑制细胞衰老的潜在分子机制是通过抑制 ROS/MAP2K6/p38 信号通路介导的。总之,这些发现表明,lncRNA MAGI2-AS3 的下调通过稳定 HSPA8 蛋白水平降低了 H 2 O 2含量并延迟了细胞衰老,从而确定了潜在的抗衰老应用。

更新日期:2022-07-05
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