Sexually dimorphic RNA helicases DDX3X and DDX3Y differentially regulate RNA metabolism through phase separation
Description
Sex differences are pervasive in human health and disease. One of the major keys to sex-biased differences lies in the sex chromosomes, which encode a group of sex-specific protein homologs. 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 regulation of RNA translation and in their propensities for liquid-liquid phase separation (LLPS) and dissolution. 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 to DDX3X contributes to the slower disassembly dynamics of DDX3Y-positive condensates and stress granules (SGs). Importantly, DDX3X- and DDX3Y-positive SGs have common and unique mRNA targets, and DDX3Y-dependent LLPS represses mRNA translation more strongly than DDX3X-dependent LLPS. Lastly, we show that DDX3Y enhances the aggregation of FUS, an RNA-binding protein implicated in amyotrophic lateral sclerosis, more strongly than DDX3X. 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.
Files
Steps to reproduce
Please check the Method section of the related paper.