Institute of Molecular Biology and Medicine, Université Libre de Bruxelles, 6041 Charleroi, Belgium.
Present address: Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, 52074 Aachen, Germany.
Cells. 2020 Jul 10;9(7):1666. doi: 10.3390/cells9071666.
The interaction of oncogenes with cellular proteins is a major determinant of cellular transformation. The NUP98-HOXA9 and SET-NUP214 chimeras result from recurrent chromosomal translocations in acute leukemia. Functionally, the two fusion proteins inhibit nuclear export and interact with epigenetic regulators. The full interactome of NUP98-HOXA9 and SET-NUP214 is currently unknown. We used proximity-dependent biotin identification (BioID) to study the landscape of the NUP98-HOXA9 and SET-NUP214 environments. Our results suggest that both fusion proteins interact with major regulators of RNA processing, with translation-associated proteins, and that both chimeras perturb the transcriptional program of the tumor suppressor p53. Other cellular processes appear to be distinctively affected by the particular fusion protein. NUP98-HOXA9 likely perturbs Wnt, MAPK, and estrogen receptor (ER) signaling pathways, as well as the cytoskeleton, the latter likely due to its interaction with the nuclear export receptor CRM1. Conversely, mitochondrial proteins and metabolic regulators are significantly overrepresented in the SET-NUP214 proximal interactome. Our study provides new clues on the mechanistic actions of nucleoporin fusion proteins and might be of particular relevance in the search for new druggable targets for the treatment of nucleoporin-related leukemia.
癌基因与细胞蛋白的相互作用是细胞转化的主要决定因素。NUP98-HOXA9 和 SET-NUP214 嵌合体是急性白血病中反复染色体易位的结果。从功能上讲，这两种融合蛋白抑制核输出并与表观遗传调节剂相互作用。NUP98-HOXA9 和 SET-NUP214 的全互作组目前尚不清楚。我们使用邻近依赖性生物素鉴定（BioID）来研究 NUP98-HOXA9 和 SET-NUP214 环境的全景。我们的结果表明，两种融合蛋白都与 RNA 加工的主要调节剂、与翻译相关的蛋白相互作用，并且两种嵌合体都扰乱了肿瘤抑制因子 p53 的转录程序。其他细胞过程似乎明显受到特定融合蛋白的影响。NUP98-HOXA9 可能扰乱 Wnt、MAPK 和雌激素受体 (ER) 信号通路，以及细胞骨架，后者可能是由于其与核输出受体 CRM1 的相互作用。相反，线粒体蛋白和代谢调节剂在 SET-NUP214 的近端互作组中显著过表达。我们的研究为核孔蛋白融合蛋白的作用机制提供了新的线索，并且在寻找核孔相关白血病的新治疗靶点方面可能具有特别重要的意义。
