A 5' UTR GGN repeat controls localisation and translation of a potassium leak channel mRNA through G-quadruplex formation.
A 5' UTR GGN repeat controls localisation and translation of a potassium leak channel mRNA through G-quadruplex formation.
复制标题
DOI：
10.1093/nar/gkaa699
复制
发表时间：
2020-09-25
影响因子：
14.9
通讯作者：
Coldwell MJ
中科院分区：
文献类型：
--
作者：
Maltby CJ;Schofield JPR;Houghton SD;O'Kelly I;Vargas-Caballero M;Deinhardt K;Coldwell MJ
RNA G-四链体（G4）是一种二级结构，被认为是转录后mRNA定位和翻译的调节因子。已知一些神经元mRNA内的G4控制远端定位和局部翻译，有助于促进归因于正常细胞功能的突触重塑的不同局部蛋白质组。在这项研究中，我们研究了在钾2孔结构域泄漏通道Task 3 mRNA的5′ UTR内发现的（GGN）13重复序列的G4形成。生物物理学分析表明，该（GGN）13重复序列在体外形成平行的G4，表现出G4的典型钾特异性，在生理离子条件下保持热稳定。通过小鼠脑组织G4-RNA免疫沉淀，我们进一步证实了Task 3 mRNA在体内形成G4结构。G4在体外抑制Task 3的翻译，并通过G4特异性解旋酶DHX 36的活性克服，增加HEK 293细胞中的K+漏电流和膜超极化。此外，我们观察到，这G4是根本，以确保交付任务3 mRNA远端初级皮质神经突。研究表明，异常的Task 3表达与神经元功能障碍相关，因此，我们认为这种G4在调节维持神经元内K+渗漏的Task 3渗漏通道的局部表达中是重要的。
RNA G-quadruplexes (G4s) are secondary structures proposed to function as regulators of post-transcriptional mRNA localisation and translation. G4s within some neuronal mRNAs are known to control distal localisation and local translation, contributing to distinct local proteomes that facilitate the synaptic remodelling attributed to normal cellular function. In this study, we characterise the G4 formation of a (GGN)13 repeat found within the 5′ UTR of the potassium 2-pore domain leak channel Task3 mRNA. Biophysical analyses show that this (GGN)13 repeat forms a parallel G4 in vitro exhibiting the stereotypical potassium specificity of G4s, remaining thermostable under physiological ionic conditions. Through mouse brain tissue G4-RNA immunoprecipitation, we further confirm that Task3 mRNA forms a G4 structure in vivo. The G4 is inhibitory to translation of Task3 in vitro and is overcome through activity of a G4-specific helicase DHX36, increasing K+ leak currents and membrane hyperpolarisation in HEK293 cells. Further, we observe that this G4 is fundamental to ensuring delivery of Task3 mRNA to distal primary cortical neurites. It has been shown that aberrant Task3 expression correlates with neuronal dysfunction, we therefore posit that this G4 is important in regulated local expression of Task3 leak channels that maintain K+ leak within neurons.
登录
查看更多内容
影响因子：
21.8
作者：
Di Antonio M;Ponjavic A;Radzevičius A;Ranasinghe RT;Catalano M;Zhang X;Shen J;Needham LM;Lee SF;Klenerman D;Balasubramanian S
通讯作者：
Balasubramanian S
影响因子：
14.9
作者：
Bugaut A;Balasubramanian S
通讯作者：
Balasubramanian S
影响因子：
64.8
作者：
Chen MC;Tippana R;Demeshkina NA;Murat P;Balasubramanian S;Myong S;Ferré-D'Amaré AR
通讯作者：
Ferré-D'Amaré AR
影响因子：
3.7
作者：
Bando, Yuki;Hirano, Tomoo;Tagawa, Yoshiaki
通讯作者：
Tagawa, Yoshiaki
G-四链体折叠和稳定性中的金属阳离子。
影响因子：
5.5
作者：
Bhattacharyya D;Mirihana Arachchilage G;Basu S
通讯作者：
Basu S