Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Graduate Group in Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Mol Cell. 2022 Jul 21;82(14):2588-2603.e9. doi: 10.1016/j.molcel.2022.04.022. Epub 2022 May 18.
Sex differences are pervasive in human health and disease. One major key to sex-biased differences lies in the sex chromosomes. Although the functions of the X chromosome proteins are well appreciated, how they compare with their Y chromosome homologs remains elusive. Herein, using ensemble and single-molecule techniques, we report that the sex chromosome-encoded RNA helicases DDX3X and DDX3Y are distinct in their propensities for liquid-liquid phase separation (LLPS), dissolution, and translation repression. We demonstrate that the N-terminal intrinsically disordered region of DDX3Y more strongly promotes LLPS than the corresponding region of DDX3X and that the weaker ATPase activity of DDX3Y, compared with DDX3X, contributes to the slower disassembly dynamics of DDX3Y-positive condensates. Interestingly, DDX3Y-dependent LLPS represses mRNA translation and enhances aggregation of FUS more strongly than DDX3X-dependent LLPS. Our study provides a platform for future comparisons of sex chromosome-encoded protein homologs, providing insights into sex differences in RNA metabolism and human disease.
性别差异在人类健康和疾病中普遍存在。导致性别偏向差异的一个主要关键因素在于性染色体。尽管 X 染色体蛋白的功能已得到充分了解，但它们与 Y 染色体同源物的比较仍不清楚。在这里，我们使用集合和单分子技术报告说，性染色体编码的 RNA 解旋酶 DDX3X 和 DDX3Y 在液-液相分离（LLPS）、溶解和翻译抑制方面存在明显差异。我们证明，DDX3Y 的 N 端固有无序区域比 DDX3X 的相应区域更强烈地促进 LLPS，并且与 DDX3X 相比，DDX3Y 的较弱的 ATP 酶活性有助于 DDX3Y 阳性凝聚物的较慢拆卸动力学。有趣的是，DDX3Y 依赖性的 LLPS 比 DDX3X 依赖性的 LLPS 更强烈地抑制 mRNA 翻译并增强 FUS 的聚集。我们的研究为未来比较性染色体编码蛋白同源物提供了一个平台，为 RNA 代谢和人类疾病中的性别差异提供了见解。
