Laboratory of Viral Interactomes, GIGA Institute, University of Liege, Liege, Belgium.
Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
PLoS Pathog. 2021 Sep 20;17(9):e1009919. doi: 10.1371/journal.ppat.1009919. eCollection 2021 Sep.
Viral infections are known to hijack the transcription and translation of the host cell. However, the extent to which viral proteins coordinate these perturbations remains unclear. Here we used a model system, the human T-cell leukemia virus type 1 (HTLV-1), and systematically analyzed the transcriptome and interactome of key effectors oncoviral proteins Tax and HBZ. We showed that Tax and HBZ target distinct but also common transcription factors. Unexpectedly, we also uncovered a large set of interactions with RNA-binding proteins, including the U2 auxiliary factor large subunit (U2AF2), a key cellular regulator of pre-mRNA splicing. We discovered that Tax and HBZ perturb the splicing landscape by altering cassette exons in opposing manners, with Tax inducing exon inclusion while HBZ induces exon exclusion. Among Tax- and HBZ-dependent splicing changes, we identify events that are also altered in Adult T cell leukemia/lymphoma (ATLL) samples from two independent patient cohorts, and in well-known cancer census genes. Our interactome mapping approach, applicable to other viral oncogenes, has identified spliceosome perturbation as a novel mechanism coordinated by Tax and HBZ to reprogram the transcriptome.
病毒感染已知会劫持宿主细胞的转录和翻译。然而，病毒蛋白在多大程度上协调这些干扰仍然不清楚。在这里，我们使用了一个模型系统，即人类 T 细胞白血病病毒 1 型（HTLV-1），并系统地分析了关键致癌蛋白 Tax 和 HBZ 的转录组和互作组。我们表明，Tax 和 HBZ 靶向不同但也有共同的转录因子。出乎意料的是，我们还发现了与 RNA 结合蛋白的大量相互作用，包括 U2 辅助因子大亚基（U2AF2），这是一种细胞内前体 mRNA 剪接的关键调节剂。我们发现，Tax 和 HBZ 通过以相反的方式改变剪接体外显子来扰乱剪接景观，Tax 诱导外显子包含，而 HBZ 诱导外显子排除。在 Tax 和 HBZ 依赖性剪接变化中，我们鉴定了在来自两个独立患者队列的成人 T 细胞白血病/淋巴瘤（ATLL）样本中以及在众所周知的癌症普查基因中也发生改变的事件。我们的互作组图谱方法适用于其他病毒致癌基因，已确定剪接体干扰是 Tax 和 HBZ 协调重编程转录组的一种新机制。
