The effects of NCBP3 on METTL3-mediated m6A RNA methylation to enhance translation process in hypoxic cardiomyocytes.
The effects of NCBP3 on METTL3-mediated m6A RNA methylation to enhance translation process in hypoxic cardiomyocytes.
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NCBP3 对 METTL3 介导的 m6A RNA 甲基化的影响，以增强缺氧心肌细胞的翻译过程
DOI：
10.1111/jcmm.16852
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发表时间：
2021-09
影响因子：
5.3
通讯作者：
Zhang Z
中科院分区：
文献类型：
--
作者：
Ye F;Wang X;Tu S;Zeng L;Deng X;Luo W;Zhang Z
缺氧作为一种重要的致病因素，常对心脏损伤和功能障碍产生巨大的危害。我们先前的研究已经通过RNA测序和核糖体分析测序揭示了体外和体内心肌细胞对缺氧反应的整体转录组和翻译组谱。我们观察到一系列转录和翻译之间的差异表达基因，这可能归因于靶基因5'非翻译区的核帽结合亚基3（NCBP 3）的缺氧特异性结合亲和力。尽管我们观察到NCBP 3可以促进缺氧应激下心肌的翻译过程，但NCBP 3调节基因翻译的潜在分子机制仍不清楚。在本研究中，我们进行了NCBP 3免疫沉淀质谱，发现在缺氧大鼠H9 C2心肌细胞中，胃L3和eIF 4A 2特别与NCBP 3相互作用。此外，我们观察到，在缺氧时，胃L3介导的N6-甲基腺苷（m6 A）甲基化升高，但受到NCBP 3或胃L3敲低的影响。最后，我们还证明了NCBP 3/心肌L3/eIF 4A 2调节轴在心肌细胞经历缺氧应激中起着特定的作用。总之，我们揭示了NCBP 3，一种新的缺氧特异性反应蛋白，作为一种支架，协调心肌L3和eIF 4A 2，在缺氧应激时通过心肌细胞中的m6 A RNA甲基化增强基因翻译。
Hypoxia as a crucial pathogenesis factor usually results in huge harmful effects on cardiac injury and dysfunction. Our previous study has uncovered the global transcriptome and translatome profiles of cardiomyocytes in vitro and in vivo to response to hypoxia by RNA sequencing and ribosome profiling sequencing. We observe a series of differential expressed genes between transcription and translation, which may be attributed to the hypoxia‐specific binding affinity of nuclear cap‐binding subunit 3 (NCBP3) at 5' untranslation region of target genes. Although we observe that NCBP3 can facilitate translational process in myocardium under hypoxia stress, the underlying molecular mechanism of NCBP3 for gene translation modulation remains unclear. In this study, we performed NCBP3 immunoprecipitation for mass spectrum and found that METTL3 and eIF4A2 particularly interacted with NCBP3 in hypoxic rat H9C2 cardiomyocytes. Furthermore, we observed that METTL3‐mediated N6‐methyladenosine (m6A) methylation was elevated in hypoxia, but compromised by NCBP3 or METTL3 knockdown. Finally, we also demonstrated that NCBP3/METTL3/eIF4A2 regulatory axis plays a specific role in cardiomyocytes undergoing hypoxic stress. Taken together, we unmasked NCBP3, a novel hypoxia‐specific response protein functions as a scaffold to coordinate METTL3 and eIF4A2 for enhancing gene translation by m6A RNA methylation in cardiomyocytes upon hypoxic stress.
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