DNA结合和有丝分裂磷酸化保护聚谷氨酰胺蛋白免于组装形成，这一成果由美国斯坦福大学医学院Joanna Wysocka研究小组经过不懈努力而取得。相关论文于2025年4月15日发表于国际顶尖学术期刊《细胞》杂志上。

研究小组探索FOXP2和其他富含谷氨酰胺的tf如何避免计划外组装。在整个间期，DNA结合，无论序列特异性如何，都具有溶解作用。在有丝分裂过程中，多重磷酸化事件促进FOXP2从染色质中被驱逐并取代DNA的溶解功能。此外，与语言进化相关的人类特异性氨基酸替换映射到有丝分裂磷酸化补丁，即“EVO补丁”，并降低了人类FOXP2组装的倾向。将致病形式的亨廷顿蛋白修饰为DNA结合结构域、EVO贴片的拟磷变体或带负电荷的肽，足以减少组装的形成，这表明控制富含谷氨酰胺的TFs溶解度的劫持机制可能为治疗多Q扩增性疾病提供新的策略。

据了解，在神经退行性疾病中，聚谷氨酰胺（polyQ）扩增与致病性蛋白聚集有关。然而，在许多转录因子（TF）中也发现了长多Q束，例如FOXP2，一种与人类语言有关的TF。

附：英文原文

Title: DNA binding and mitotic phosphorylation protect polyglutamine proteins from assembly formation

Author: Shady Saad, Tomek Swigut, Saman Tabatabaee, Pranav Lalgudi, Daniel F. Jarosz, Joanna Wysocka

Issue&Volume: 2025-04-15

Abstract: Polyglutamine (polyQ) expansion is associated with pathogenic protein aggregation in neurodegenerative disorders. However, long polyQ tracts are also found in many transcription factors (TFs), such as FOXP2, a TF implicated in human speech. Here, we explore how FOXP2 and other glutamine-rich TFs avoid unscheduled assembly. Throughout interphase, DNA binding, irrespective of sequence specificity, has a solubilizing effect. During mitosis, multiple phosphorylation events promote FOXP2’s eviction from chromatin and supplant the solubilizing function of DNA. Further, human-specific amino acid substitutions linked to the evolution of speech map to a mitotic phospho-patch, the “EVO patch,” and reduce the propensity of the human FOXP2 to assemble. Fusing the pathogenic form of Huntingtin to either a DNA-binding domain, a phosphomimetic variant of this EVO patch, or a negatively charged peptide is sufficient to diminish assembly formation, suggesting that hijacking mechanisms governing solubility of glutamine-rich TFs may offer new strategies for treatment of polyQ expansion diseases.

DOI: 10.1016/j.cell.2025.03.031

Source: https://www.cell.com/cell/abstract/S0092-8674(25)00349-6