Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA
Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA.
Mol Cell Biol. 2014 Aug;34(16):2981-95. doi: 10.1128/MCB.00036-14. Epub 2014 Jun 9.
The RING domain protein Arkadia/RNF111 is a ubiquitin ligase in the transforming growth factor β (TGFβ) pathway. We previously identified Arkadia as a small ubiquitin-like modifier (SUMO)-binding protein with clustered SUMO-interacting motifs (SIMs) that together form a SUMO-binding domain (SBD). However, precisely how SUMO interaction contributes to the function of Arkadia was not resolved. Through analytical molecular and cell biology, we found that the SIMs share redundant function with Arkadia's M domain, a region distinguishing Arkadia from its paralogs ARKL1/ARKL2 and the prototypical SUMO-targeted ubiquitin ligase (STUbL) RNF4. The SIMs and M domain together promote both Arkadia's colocalization with CBX4/Pc2, a component of Polycomb bodies, and the activation of a TGFβ pathway transcription reporter. Transcriptome profiling through RNA sequencing showed that Arkadia can both promote and inhibit gene expression, indicating that Arkadia's activity in transcriptional control may depend on the epigenetic context, defined by Polycomb repressive complexes and DNA methylation.
RING 结构域蛋白 Arkadia/RNF111 是转化生长因子 β（TGFβ）通路中的一种泛素连接酶。我们之前发现 Arkadia 是一种具有聚集的小泛素样修饰物（SUMO）相互作用基序（SIMs）的 SUMO 结合蛋白，这些基序共同构成一个 SUMO 结合结构域（SBD）。然而，SUMO 相互作用如何精确地促进 Arkadia 的功能尚不清楚。通过分析分子和细胞生物学，我们发现 SIMs 与 Arkadia 的 M 结构域具有冗余功能，M 结构域是将 Arkadia 与其同源物 ARKL1/ARKL2 和典型的 SUMO 靶向泛素连接酶（STUbL）RNF4 区分开来的区域。SIMs 和 M 结构域共同促进 Arkadia 与 CBX4/Pc2 的共定位，CBX4/Pc2 是 Polycomb 体的一个组成部分，以及 TGFβ 通路转录报告基因的激活。通过 RNA 测序进行的转录组分析表明，Arkadia 既可以促进又可以抑制基因表达，这表明 Arkadia 在转录控制中的活性可能取决于表观遗传背景，由 Polycomb 抑制复合物和 DNA 甲基化定义。
