Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), Heidelberg University, Heidelberg, Germany.
Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
EMBO Rep. 2021 Mar 3;22(3):e49651. doi: 10.15252/embr.201949651. Epub 2021 Jan 22.
Molecular switches are essential modules in signaling networks and transcriptional reprogramming. Here, we describe a role for small ubiquitin-related modifier SUMO as a molecular switch in epidermal growth factor receptor (EGFR) signaling. Using quantitative mass spectrometry, we compare the endogenous SUMO proteomes of HeLa cells before and after EGF stimulation. Thereby, we identify a small group of transcriptional coregulators including IRF2BP1, IRF2BP2, and IRF2BPL as novel players in EGFR signaling. Comparison of cells expressing wild type or SUMOylation-deficient IRF2BP1 indicates that transient deSUMOylation of IRF2BP proteins is important for appropriate expression of immediate early genes including dual specificity phosphatase 1 (DUSP1, MKP-1) and the transcription factor ATF3. We find that IRF2BP1 is a repressor, whose transient deSUMOylation on the DUSP1 promoter allows-and whose timely reSUMOylation restricts-DUSP1 transcription. Our work thus provides a paradigm how comparative SUMO proteome analyses serve to reveal novel regulators in signal transduction and transcription.
分子开关是信号网络和转录重编程的基本模块。在这里，我们描述了小泛素相关修饰物 SUMO 作为表皮生长因子受体 (EGFR) 信号转导中的分子开关的作用。我们使用定量质谱法比较了 EGF 刺激前后 HeLa 细胞中的内源性 SUMO 蛋白质组。由此，我们确定了一小群转录共调节剂，包括 IRF2BP1、IRF2BP2 和 IRF2BPL，作为 EGFR 信号转导中的新成员。比较表达野生型或 SUMOylation 缺陷型 IRF2BP1 的细胞表明，IRF2BP 蛋白的瞬时去 SUMOylation 对于包括双特异性磷酸酶 1（DUSP1，MKP-1）和转录因子 ATF3 在内的即刻早期基因的适当表达很重要。我们发现 IRF2BP1 是一种抑制剂，其在 DUSP1 启动子上的瞬时去 SUMOylation 允许 - 并且其及时的再 SUMOylation 限制 - DUSP1 转录。因此，我们的工作提供了一个范例，说明了比较 SUMO 蛋白质组分析如何揭示信号转导和转录中的新调节剂。
