Acetylation of intrinsically disordered regions regulates phase separation.,Nature Chemical Biology

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Acetylation of intrinsically disordered regions regulates phase separation.
Nature Chemical Biology ( IF 12.9 ) Pub Date : 2018-12-10 , DOI: 10.1038/s41589-018-0180-7
Makoto Saito _{1,

2} , Daniel Hess ₁ , Jan Eglinger ₁ , Anatol W Fritsch _{3,

4} , Moritz Kreysing _{3,

4} , Brian T Weinert ₅ , Chunaram Choudhary ₅ , Patrick Matthias _{1,

2}

Affiliation

Liquid-liquid phase separation (LLPS) of proteins containing intrinsically disordered regions (IDRs) has been proposed as a mechanism underlying the formation of membrane-less organelles. Tight regulation of IDR behavior is essential to ensure that LLPS only takes place when necessary. Here, we report that IDR acetylation/deacetylation regulates LLPS and assembly of stress granules (SGs), membrane-less organelles forming in response to stress. Acetylome analysis revealed that the RNA helicase DDX3X, an important component of SGs, is a novel substrate of the deacetylase HDAC6. The N-terminal IDR of DDX3X (IDR1) can undergo LLPS in vitro, and its acetylation at multiple lysine residues impairs the formation of liquid droplets. We also demonstrated that enhanced LLPS propensity through deacetylation of DDX3X-IDR1 by HDAC6 is necessary for SG maturation, but not initiation. Our analysis provides a mechanistic framework to understand how acetylation and deacetylation of IDRs regulate LLPS spatiotemporally, and impact membrane-less organelle formation in vivo.

中文翻译：

内在无序区域的乙酰化调节相分离。

含有内在无序区（IDR）的蛋白质的液相-液相分离（LLPS）已被提议为无膜细胞器形成的基础。严格控制IDR行为对于确保仅在必要时才进行LLPS至关重要。在这里，我们报告IDR乙酰化/脱乙酰化调节LLPS和应力颗粒（SGs）组装，形成无膜细胞器以应对压力。乙酰酶组分析显示，RNA解旋酶DDX3X是SGs的重要组成部分，是脱乙酰基酶HDAC6的新型底物。DDX3X（IDR1）的N端IDR可以在体外进行LLPS，其在多个赖氨酸残基处的乙酰化会削弱液滴的形成。我们还证明了通过HDAC6使DDX3X-IDR1脱乙酰化来增强LLPS倾向对于SG成熟是必要的，但不是引发作用。我们的分析提供了一个机制框架，以了解IDR的乙酰化和脱乙酰化如何时空调节LLPS，并影响体内无膜细胞器的形成。

更新日期：2019-01-25

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