Cytoplasmic nucleic acid-based XNAs directly enhance live cardiac cell function by a Ca2+ cycling-independent mechanism via the sarcomere.
Cytoplasmic nucleic acid-based XNAs directly enhance live cardiac cell function by a Ca2+ cycling-independent mechanism via the sarcomere.
复制标题
基于细胞质核酸的 XNA 通过肌节的 Ca2 循环独立机制直接增强活心脏细胞功能。
DOI：
10.1016/j.yjmcc.2019.02.016
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发表时间：
2019
影响因子：
5
通讯作者：
Metzger,JosephM
中科院分区：
文献类型：
--
作者：
Thompson,BrianR;Soller,KaileyJ;Vetter,Anthony;Yang,Jing;Veglia,Gianluigi;Bowser,MichaelT;Metzger,JosephM
核酸-蛋白质相互作用对于调节细胞核中的基因活化是至关重要的。然而，在细胞质中，潜在的核酸-蛋白质功能相互作用不太清楚。大量和不断增加的非编码RNA和DNA片段的出现增加了细胞质核酸可能与细胞质细胞组分相互作用以直接改变细胞内关键生物过程的可能性。我们现在表明，天然和合成的核酸，统称XNAs，当被引入到活细胞心肌细胞的细胞质中时，通过一种机制显着增强收缩功能，该机制独立于新的翻译、TLR-9通路的激活或细胞内Ca 2+循环的改变。研究结果显示，对于细胞质XNA，XNA寡核苷酸长度依赖性很强，但不依赖于序列或核酸部分，从而加速肌细胞松弛。XNAs以条纹图案定位于肌节，并以静电依赖性方式以高亲和力结合心肌肌钙蛋白调节复合物。从机制上讲，XNAs表型复制基于PKA的修饰肌钙蛋白，以引起更快的松弛。总的来说，这些数据支持细胞质核酸在直接调节活细胞心脏性能中的新作用，并提高了细胞质核酸-蛋白质相互作用可能改变其他细胞类型中功能相关途径的可能性。
Nucleic acid - protein interactions are critical for regulating gene activation in the nucleus. In the cytoplasm, however, potential nucleic acid-protein functional interactions are less clear. The emergence of a large and expanding number of non-coding RNAs and DNA fragments raises the possibility that the cytoplasmic nucleic acids may interact with cytoplasmic cellular components to directly alter key biological processes within the cell. We now show that both natural and synthetic nucleic acids, collectively XNAs, when introduced to the cytoplasm of live cell cardiac myocytes, markedly enhance contractile function via a mechanism that is independent of new translation, activation of the TLR-9 pathway or by altered intracellular Ca2+cycling. Findings show a steep XNA oligo length-dependence, but not sequence dependence or nucleic acid moiety dependence, for cytoplasmic XNAs to hasten myocyte relaxation. XNAs localized to the sarcomere in a striated pattern and bound the cardiac troponin regulatory complex with high affinity in an electrostatic-dependent manner. Mechanistically, XNAs phenocopy PKA-based modified troponin to cause faster relaxation. Collectively, these data support a new role for cytoplasmic nucleic acids in directly modulating live cell cardiac performance and raise the possibility that cytoplasmic nucleic acid - protein interactions may alter functionally relevant pathways in other cell types.