Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA.
Nat Commun. 2024 Nov 3;15(1):9492. doi: 10.1038/s41467-024-53761-w.
The Human Silencing Hub (HuSH) complex silences retrotransposable elements in vertebrates. Here, we identify a second HuSH complex, designated HuSH2, which is centered around TASOR2, a paralog of the core TASOR protein in HuSH. Our findings reveal that HuSH and HuSH2 localize to distinct and non-overlapping genomic loci. Specifically, HuSH localizes to and represses LINE-1 retrotransposons, whereas HuSH2 targets and represses KRAB-ZNFs and interferon signaling and response genes. We use in silico protein structure predictions to simulate MPP8 interactions with TASOR paralogs, guiding amino acid substitutions that disrupted binding to HuSH complexes. These MPP8 transgenes and other constructs reveal the importance of HuSH complex quantities in regulating LINE-1 activity. Furthermore, our results suggest that dynamic changes in TASOR and TASOR2 expression enable cells to finely tune HuSH-mediated silencing. This study offers insights into the interplay of HuSH complexes, highlighting their vital role in retrotransposon regulation.
人类沉默中心（HuSH）复合物在脊椎动物中沉默逆转录转座子。在这里，我们鉴定了第二个 HuSH 复合物，命名为 HuSH2，它以 TASOR2 为中心，TASOR2 是 HuSH 中核心 TASOR 蛋白的同源物。我们的研究结果表明，HuSH 和 HuSH2 定位于不同且不重叠的基因组位置。具体来说，HuSH 定位于并抑制 LINE-1 逆转录转座子，而 HuSH2 靶向并抑制 KRAB-ZNFs 和干扰素信号转导和应答基因。我们使用计算机蛋白质结构预测来模拟 MPP8 与 TASOR 同源物的相互作用，指导氨基酸取代破坏与 HuSH 复合物的结合。这些 MPP8 转基因和其他构建体揭示了 HuSH 复合物数量在调节 LINE-1 活性中的重要性。此外，我们的结果表明，TASOR 和 TASOR2 表达的动态变化使细胞能够精细地调节 HuSH 介导的沉默。这项研究提供了对 HuSH 复合物相互作用的深入了解，强调了它们在逆转录转座子调控中的重要作用。
