Variable Glutamine-Rich Repeats Modulate Transcription Factor Activity.
Variable Glutamine-Rich Repeats Modulate Transcription Factor Activity.
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富含谷氨酰胺的可变重复序列调节转录因子活性。
DOI：
10.1016/j.molcel.2015.07.003
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发表时间：
2015-08-20
期刊：
影响因子：
16
通讯作者：
Verstrepen KJ
中科院分区：
文献类型：
--
作者：
Gemayel R;Chavali S;Pougach K;Legendre M;Zhu B;Boeynaems S;van der Zande E;Gevaert K;Rousseau F;Schymkowitz J;Babu MM;Verstrepen KJ
人类各种蛋白质中富含谷氨酰胺(Q)的重复序列过度扩张，已知会导致严重的神经退行性疾病，如亨廷顿病和几种共济失调。然而，这些重复序列的生理作用以及更温和的重复序列变异的后果仍不清楚。在这里，我们证明了富Q结构域在真核转录因子中高度丰富，在那里它们扮演着功能调节器的角色。酵母转录调控因子SSN6(Cyc8)重复数的递增变化导致目标基因表达的系统性、重复长度相关的变化，从而导致直接的表型变化。SSN6的功能随着其重复次数的增加而增加，直到达到一定的阈值，在该阈值下进一步扩展导致聚集。定量蛋白质组学分析表明，SSN6重复序列影响其溶解性以及与Tup1和其他调节因子的相互作用。因此，富含Q的重复序列是动态的功能域，它调节调节因子的固有功能，具有致病重复序列扩张的固有风险。富含谷氨酰胺的重复序列在真核生物中高度丰富，在真菌转录因子中的重复序列变异，其靶标的表达发生变化，可变重复序列能够调节转录因子的溶解性和相互作用，过度的重复序列扩张导致TF功能障碍和聚集，调节蛋白中丰富的谷氨酰胺重复序列结构域扩张与毁灭性的神经退行性疾病相关。然而，Gemayel等人。表明这些高度可变的富含谷氨酰胺的重复序列也通过调节它们通常驻留的转录调节因子的溶解性、相互作用和功能而发挥功能作用。
Excessive expansions of glutamine (Q)-rich repeats in various human proteins are known to result in severe neurodegenerative disorders such as Huntington’s disease and several ataxias. However, the physiological role of these repeats and the consequences of more moderate repeat variation remain unknown. Here, we demonstrate that Q-rich domains are highly enriched in eukaryotic transcription factors where they act as functional modulators. Incremental changes in the number of repeats in the yeast transcriptional regulator Ssn6 (Cyc8) result in systematic, repeat-length-dependent variation in expression of target genes that result in direct phenotypic changes. The function of Ssn6 increases with its repeat number until a certain threshold where further expansion leads to aggregation. Quantitative proteomic analysis reveals that the Ssn6 repeats affect its solubility and interactions with Tup1 and other regulators. Thus, Q-rich repeats are dynamic functional domains that modulate a regulator’s innate function, with the inherent risk of pathogenic repeat expansions. Glutamine-rich repeats are highly enriched in eukaryotic transcriptional regulators Repeat variation in a fungal transcription factor changes expression of its targets Variable repeats enable tuning of transcription factor solubility and interactions Excessive repeat expansion results in TF malfunctioning and aggregation Expanded glutamine-rich repeat domains within regulatory proteins are associated with devastating neurodegenerative diseases. However, Gemayel et al. show that these highly variable glutamine-rich repeats also have a functional role by modulating the solubility, interactions, and function of the transcriptional regulators in which they typically reside.