Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Suwon 16419, Korea.
Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Suwon 16419, Korea
Proc Natl Acad Sci U S A. 2021 Dec 14;118(50). doi: 10.1073/pnas.2109668118.
Heterogeneous nuclear ribonucleoproteins (hnRNPs) represent a large family of RNA-binding proteins that control key events in RNA biogenesis under both normal and diseased cellular conditions. The low-complexity (LC) domain of hnRNPs can become liquid-like droplets or reversible amyloid-like polymers by phase separation. Yet, whether phase separation of the LC domains contributes to physiological functions of hnRNPs remains unclear. hnRNPH1 contains two LC domains, LC1 and LC2. Here, we show that reversible phase separation of the LC1 domain is critical for both interaction with different kinds of RNA-binding proteins and control of the alternative-splicing activity of hnRNPH1. Interestingly, although not required for phase separation, the LC2 domain contributes to the robust transcriptional activation of hnRNPH1 when fused to the DNA-binding domain, as found recently in acute lymphoblastic leukemia. Our data suggest that the ability of the LC1 domain to phase-separate into reversible polymers or liquid-like droplets is essential for function of hnRNPH1 as an alternative RNA-splicing regulator, whereas the LC2 domain may contribute to the aberrant transcriptional activity responsible for cancer transformation.
异质核核糖核蛋白 (hnRNPs) 是一大类 RNA 结合蛋白家族，它们在正常和患病细胞条件下控制 RNA 生物发生中的关键事件。hnRNPs 的低复杂度 (LC) 结构域可以通过相分离形成液态样液滴或可逆的类淀粉样聚合物。然而，LC 结构域的相分离是否有助于 hnRNPs 的生理功能尚不清楚。hnRNPH1 包含两个 LC 结构域，LC1 和 LC2。在这里，我们表明 LC1 结构域的可逆相分离对于与不同种类的 RNA 结合蛋白的相互作用以及 hnRNPH1 的可变剪接活性的控制都是至关重要的。有趣的是，尽管 LC2 结构域不是相分离所必需的，但正如最近在急性淋巴细胞白血病中发现的那样，当与 DNA 结合结构域融合时，LC2 结构域有助于 hnRNPH1 的强大转录激活。我们的数据表明，LC1 结构域形成可逆聚合物或液态样液滴的相分离能力对于 hnRNPH1 作为替代 RNA 剪接调节剂的功能至关重要，而 LC2 结构域可能有助于导致癌症转化的异常转录活性。
