The N6-methyladenosine mRNA methylase METTL14 promotes renal ischemic reperfusion injury via suppressing YAP1
The N6-methyladenosine mRNA methylase METTL14 promotes renal ischemic reperfusion injury via suppressing YAP1
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N6-甲基腺苷mRNA甲基化酶METTL14通过抑制YAP1促进肾缺血再灌注损伤
DOI：
10.1002/jcb.29258
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发表时间：
2019-07-18
影响因子：
4
通讯作者：
Mou, Shan
中科院分区：
文献类型：
--
作者：
Xu, Yao;Yuan, Xiao Dong;Mou, Shan
肾缺血再灌注损伤（IRI）是急性肾损伤（阿基）最常见的原因之一，与高发病率和死亡率密切相关。然而，肾IRI的发病机制是复杂的，并没有完全确定。N6-甲基腺苷（m6 A）是近年来发现的一种存在于哺乳动物信使RNA中的重要修饰。它涉及各种生物学过程，而m6 A在IRI中的作用没有说明。在这里，我们表明，在人类阿基肾组织和IRI HK-2细胞中，m6 A-甲基化RNA水平及其甲基转移酶L14升高。此外，在体外和体内，胃L14敲低保护肾脏免受IRI。从机制上讲，我们确定YAP 1是阿基进展中胃L14的直接靶点。通过肽17抑制YAP 1-TEAD信号传导消除了胃L14在体外和体内针对IRI的保护作用。综上所述，这些结果表明N6-甲基腺苷mRNA甲基化酶胃L14通过抑制YAP 1促进肾IRI。胃L14-YAP 1通路的发现为理解阿基提供了重要的新视角，有助于揭示新的治疗策略和靶点。
Renal ischemia-reperfusion injury (IRI) is one of the most common causes of acute kidney injury (AKI), which is closely related to high morbidity and mortality. However, the pathogenesis underlying renal IRI is complex and not fully defined. N6-methyladenosine (m6A) was recently found to be an abundant modification in mammalian messenger RNAs. It is implicated in various biological processes, while the role of m6A in IRI is not illustrated. Here we show that the m6A-methylated RNA level and its methyltransferase METTL14 are elevated in human AKI renal tissues and IRI HK-2 cells. Moreover, METTL14 knockdown protects the kidney against IRI in vitro and in vivo. Mechanistically, we identified that YAP1 is a direct target of METTL14 in AKI progression. Inhibition of YAP1-TEAD signaling by peptide 17 abrogates the protective effect of METTL14 against IRI in vitro and in vivo. Taken together, these results reveal that the N6-methyladenosine mRNA methylase METTL14 promotes the renal IRI via suppressing YAP1. The discovery of the METTL14-YAP1 pathway provides an important new perspective for understanding AKI and is conducive to revealing new therapeutic strategies and targets.