Ablation of long noncoding RNA MALAT1 activates antioxidant pathway and alleviates sepsis in mice.
Ablation of long noncoding RNA MALAT1 activates antioxidant pathway and alleviates sepsis in mice.
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DOI：
10.1016/j.redox.2022.102377
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发表时间：
2022-08
期刊：
影响因子：
11.4
通讯作者：
Tian, Yanan
中科院分区：
文献类型：
--
作者：
Chen, Jingshu;Tang, Shu;Ke, Sui;Cai, James J.;Osorio, Daniel;Golovko, Andrei;Morpurgo, Benjamin;Guo, Shaodong;Sun, Yuxiang;Winkle, Melanie;Calin, George A.;Tian, Yanan
转移相关肺腺癌转录物1（MALAT 1）是一种长链非编码RNA（lncRNA），已知其在癌症发展和预后中的作用。在这项研究中，我们报告，MALAT 1在调节脓毒症的急性炎症反应中起着重要作用。在患者样本中，MALAT 1表达与脓毒症的严重程度呈正相关。在培养的巨噬细胞中，LPS处理显著诱导MALAT 1表达，而MALAT 1的基因消融大大降低了促炎细胞因子水平。此外，MALAT 1消融小鼠在盲肠结扎穿孔（CLP）诱导的脓毒症和LPS诱导的内毒素血症中的存活率显著增加。MALAT 1消融小鼠的一个新的和显著的特征是巨噬细胞和其他细胞类型中的ROS水平大大降低，巨噬细胞中的谷胱甘肽/氧化型谷胱甘肽（GSH/GSSG）比率增加，表明抗氧化能力增加。我们发现MALAT 1消融导致抗氧化能力增强的机制是通过甲硫氨酸腺苷转移酶2A（MAT 2A）的表转录调控激活甲硫氨酸循环。MAT 2A 3′UTR可以被已知与MALAT 1直接结合的胃L16甲基化。发现MALAT 1消融减少了MAT 2A发夹1中的甲基化并增加了MAT 2A蛋白水平。我们的研究结果表明MALAT 1-胃L16-MAT 2A相互作用轴可能是脓毒症治疗的靶点。
The metastasis-associated lung adenocarcinoma transcript1 (MALAT1) is a long noncoding RNA (lncRNA) and is known for its role in cancer development and prognosis. In this study, we report that MALAT1 plays an important role in regulating acute inflammatory responses in sepsis. In patient samples, MALAT1 expression was positively correlated with severity of sepsis. In cultured macrophages, LPS treatment significantly induced MALAT1 expression, while genetic ablation of MALAT1 greatly reduced proinflammatory cytokine levels. Furthermore, MALAT1-ablated mice had significantly increased survival rates in cecal ligation and puncture (CLP)-induced sepsis and LPS-induced endotoxemia. One novel and salient feature of MALAT1-ablated mice is greatly reduced ROS level in macrophages and other cell types and increased glutathione/oxidized glutathione (GSH/GSSG) ratio in macrophages, suggesting an increased antioxidant capacity. We showed a mechanism for MALAT1 ablation leading to enhanced antioxidant capacity is through activation of methionine cycle by epitranscriptomical regulation of methionine adenosyltransferase 2A (MAT2A). MAT2A 3′UTR can be methylated by METTL16 which was known to directly bind to MALAT1. MALAT1 ablation was found to reduce methylation in MAT2A hairpin1 and increase MAT2A protein levels. Our results suggest a MALAT1-METTL16-MAT2A interactive axis which may be targeted for treatments of sepsis.
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DOI：
10.3390/antiox11010050
发表时间：
2021-12-27
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
--
作者：
Kumar P;Osahon O;Vides DB;Hanania N;Minard CG;Sekhar RV
通讯作者：
Sekhar RV
影响因子：
10.6
作者：
Forman, Henry Jay;Zhang, Hongqiao;Rinna, Alessandra
通讯作者：
Rinna, Alessandra
影响因子：
2.7
作者：
Liu, Wei;Geng, Feng;Yu, Li
通讯作者：
Yu, Li
影响因子：
4.1
作者：
Lauinger L;Kaiser P
通讯作者：
Kaiser P
影响因子：
3.7
作者：
Huang K;Wang C;Vagts C;Raguveer V;Finn PW;Perkins DL
通讯作者：
Perkins DL