A Neuroligin Isoform Translated by circNlgn Contributes to Cardiac Remodeling
A Neuroligin Isoform Translated by circNlgn Contributes to Cardiac Remodeling
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DOI：
10.1161/circresaha.120.318364
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发表时间：
2021-08-20
影响因子：
20.1
通讯作者：
Yang, Burton B.
中科院分区：
文献类型：
--
作者：
Du, William W.;Xu, Jindong;Yang, Burton B.
背景：纤维化心脏重塑是对急性或慢性损伤的适应不良反应，导致心律失常和进行性心力衰竭。根本机制仍不清楚。我们进行了高通量 RNA 测序来分析人类心脏病中的环状 RNA 谱，并开发了转基因小鼠来探索 circNlgn 的作用。方法和结果：通过 RNA 测序，我们发现患有特定先天性心脏缺陷且心脏负荷过重的患者的心肌组织中环状神经信号 RNA (circNlgn) 高度上调。 Neuroligin 基因的反向剪接导致环状 RNA 衍生肽 (Nlgn173) 的翻译，该肽具有 9 个氨基酸的核定位基序。该基序与结构蛋白 LaminB1 的结合促进了 Nlgn173 的核定位。 CHIP 分析表明，Nlgn173 随后与 ING4（生长蛋白 4 抑制剂）和 C8orf44-SGK3（血清和糖皮质激素诱导激酶 3）启动子结合，导致异常胶原沉积、心脏成纤维细胞增殖和心肌细胞活力降低。 circNlgn 转基因小鼠的三维超声成像显示左心室功能受损，与 WT（野生型）小鼠相比，当左心室压力超负荷时，进一步受损。在 145 名患者标本中检测到 Nlgn173 的核易位、ING4 和 C8orf44-SGK3 的表达失调以及心脏纤维化的免疫组织化学标记物。通过沉默 circNlgn 或其靶标 ING4 和 SGK3，左心室压力超负荷和转基因小鼠中观察到的表型变化被消除。结论：我们证明环状 RNA 可以翻译成新的蛋白质亚型。这一过程的失调会导致心脏超负荷引起的重构中的纤维化和心力衰竭。这种机制可能对心脏病有治疗意义。
Background: Fibrotic cardiac remodeling is a maladaptive response to acute or chronic injury that leads to arrhythmia and progressive heart failure. The underlying mechanisms remain unclear. We performed high-throughput RNA sequencing to analyze circular RNA profile in human cardiac disease and developed transgenic mice to explore the roles of circNlgn. Methods and Results: Using RNA sequencing, we found that circular neuroligin RNA (circNlgn) was highly upregulated in myocardial tissues of patients with selected congenital heart defects with cardiac overload. Back-splicing of the neuroligin gene led to the translation of a circular RNA-derived peptide (Nlgn173) with a 9-amino-acid nuclear localization motif. Binding of this motif to the structural protein LaminB1 facilitated the nuclear localization of Nlgn173. CHIP analysis demonstrated subsequent binding of Nlgn173 to both ING4 (inhibitor of growth protein 4) and C8orf44-SGK3 (serum and glucocorticoid-inducible kinase-3) promoters, resulting in aberrant collagen deposition, cardiac fibroblast proliferation, and reduced cardiomyocyte viability. Three-dimensional ultrasound imaging of circNlgn-transgenic mice showed impaired left ventricular function, with further impairment when subjected to left ventricular pressure overload compared with WT (wild type) mice. Nuclear translocation of Nlgn173, dysregulated expression of ING4 and C8orf44-SGK3, and immunohistochemical markers of cardiac fibrosis were detected in a panel of 145 patient specimens. Phenotypic changes observed in left ventricular pressure overload and transgenic mice were abrogated with silencing of circNlgn or its targets ING4 and SGK3. Conclusions: We show that a circular RNA can be translated into a novel protein isoform. Dysregulation of this process contributes to fibrosis and heart failure in cardiac overload-induced remodeling. This mechanism may hold therapeutic implications for cardiac disease.