METTL3 aggravates cell damage induced by Streptococcus pneumoniae via the NEAT1/CTCF/MUC19 axis.

Dong-Bo Ma, Hui Zhang, Xi-Ling Wang, Qiu-Ge Wu
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Abstract

Disruption of the alveolar barrier can trigger acute lung injury. This study elucidated the association of methyltransferase-like 3 (METTL3) with Streptococcus pneumoniae (SP)-induced apoptosis and inflammatory injury of alveolar epithelial cells (AECs). AECs were cultured and then infected with SP. Furthermore, the expression of METTL3, interleukin (IL)-10, IL-6, tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1), mucin 19 (MUC19), N6-methyladenosine (m6A), and NEAT1 after m6A modification were detected by qRT-PCR, Western blot, and enzyme-linked immunosorbent, m6A quantification, and methylated RNA immunoprecipitation-qPCR analyses, respectively. Moreover, the subcellular localization of NEAT1 was analyzed by nuclear/cytosol fractionation assay, and the binding between NEAT1 and CCCTC-binding factor (CTCF) was also analyzed. The results of this investigation revealed that SP-induced apoptosis and inflammatory injury in AECs and upregulated METTL3 expression. In addition, the downregulation of METTL3 alleviated apoptosis and inflammatory injury in AECs. METTL3-mediated m6A modification increased NEAT1 and promoted its binding with CTCF to facilitate MUC19 transcription. NEAT1 or MUC19 overexpression disrupted their protective role of silencing METTL3 in AECs, thereby increasing apoptosis and inflammatory injury. In conclusion, this is the first study to suggest that METTL3 aggravates SP-induced cell damage via the NEAT1/CTCF/MUC19 axis.
METTL3 通过 NEAT1/CTCF/MUC19 轴加剧肺炎链球菌诱导的细胞损伤。
肺泡屏障的破坏可引发急性肺损伤。本研究阐明了甲基转移酶样3(METTL3)与肺炎链球菌(SP)诱导的肺泡上皮细胞(AECs)凋亡和炎症损伤的关系。培养肺泡上皮细胞,然后用 SP 感染。此外,METTL3、白细胞介素(IL)-10、IL-6、肿瘤坏死因子-α(TNF-α)、单核细胞趋化蛋白-1(MCP-1)、长非编码 RNA 核旁组装转录本 1(NEAT1)、粘蛋白 19(MUC19)、N6-甲基腺苷(N6-methyladenosine)和 N6-methyladenosine(N6-methyladenosine)的表达也受到了影响、通过 qRT-PCR、Western 印迹和酶联免疫吸附、m6A 定量和甲基化 RNA 免疫沉淀-qPCR 分析,分别检测了 N6-甲基腺苷(m6A)和经 m6A 修饰后的 NEAT1。此外,还通过核/胞浆分馏法分析了 NEAT1 的亚细胞定位,并分析了 NEAT1 与 CCCTC 结合因子(CTCF)的结合情况。研究结果表明,SP 可诱导 AECs 细胞凋亡和炎症损伤,并上调 METTL3 的表达。此外,下调 METTL3 可减轻 AECs 的凋亡和炎症损伤。METTL3 介导的 m6A 修饰增加了 NEAT1,并促进了 NEAT1 与 CTCF 的结合,从而促进了 MUC19 的转录。NEAT1 或 MUC19 的过表达破坏了它们在 AECs 中沉默 METTL3 的保护作用,从而增加了细胞凋亡和炎症损伤。总之,这是首次研究表明 METTL3 通过 NEAT1/CTCF/MUC19 轴加重 SP 诱导的细胞损伤。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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