Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization.
Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization.
复制标题
DOI：
10.1016/j.cell.2015.09.015
复制
发表时间：
2015-09-24
期刊：
影响因子：
64.5
通讯作者：
Taylor, J. Paul
中科院分区：
文献类型：
--
作者：
Molliex, Amandine;Temirov, Jamshid;Lee, Jihun;Coughlin, Maura;Kanagaraj, Anderson P.;Kim, Hong Joo;Mittag, Tanja;Taylor, J. Paul
应激颗粒是由RNA结合蛋白（rbp）和RNA组成的无膜细胞器。应激颗粒的功能损伤与肌萎缩性侧索硬化症、额颞叶痴呆和多系统蛋白病有关，这些疾病以rbp的纤维包涵体为特征。遗传证据表明，持续应激颗粒与病理包涵体的积累之间存在联系。在这里，我们证明了RBP hnRNPA1在低复杂性序列结构域（LCD）介导的液-液相分离（LLPS）中成为富含蛋白质的液滴。虽然hnRNPA1的LCD足以介导LLPS，但RNA识别基序在RNA存在的情况下有助于LLPS，从而产生几种调节组装的机制。重要的是，虽然LLPS不需要，但在富含蛋白质的液滴中，纤维化会增强。我们认为，lcd介导的LLPS有助于应激颗粒的组装及其液体特性，并提供了持续应激颗粒与疾病中纤维蛋白病理之间的机制联系。具有低复杂度序列结构域的rna结合蛋白的液液相分离是胁迫颗粒组装的分子基础，持续的胁迫颗粒促进病理性蛋白纤化。
Stress granules are membrane-less organelles composed of RNA-binding proteins (RBPs) and RNA. Functional impairment of stress granules has been implicated in amyotrophic lateral sclerosis, frontotemporal dementia and multisystem proteinopathy - diseases that are characterized by fibrillar inclusions of RBPs. Genetic evidence suggests a link between persistent stress granules and the accumulation of pathological inclusions. Here we demonstrate that the RBP hnRNPA1 undergoes liquid-liquid phase separation (LLPS) into protein-rich droplets mediated by a low complexity sequence domain (LCD). While the LCD of hnRNPA1 is sufficient to mediate LLPS, the RNA recognition motifs contribute to LLPS in the presence of RNA, giving rise to several mechanisms for regulating assembly. Importantly, while not required for LLPS, fibrillization is enhanced in protein-rich droplets. We suggest that LCD-mediated LLPS contributes to the assembly of stress granules and their liquid properties, and provides a mechanistic link between persistent stress granules and fibrillar protein pathology in disease. Liquid-liquid phase separation by RNA-binding proteins harboring low complexity sequence domains is the molecular basis for stress granule assembly, and persistent stress granules promote pathological protein fibrillization.
登录
查看更多内容
影响因子：
56.9
作者：
Kwiatkowski, T. J., Jr.;Bosco, D. A.;Brown, R. H., Jr.
通讯作者：
Brown, R. H., Jr.
影响因子：
11.2
作者：
Hackman, Peter;Sarparanta, Jaakko;Udd, Bjarne
通讯作者：
Udd, Bjarne
影响因子：
64.5
作者：
Buchan, J. Ross;Kolaitis, Regina-Maria;Parker, Roy
通讯作者：
Parker, Roy
DOI：
10.1073/pnas.1504822112
发表时间：
2015-06-09
影响因子：
11.1
作者：
Elbaum-Garfinkle, Shana;Kim, Younghoon;Brangwynne, Clifford P.
通讯作者：
Brangwynne, Clifford P.
影响因子：
5.3
作者：
Figley, Matthew D.;Bieri, Gregor;Gitler, Aaron D.
通讯作者：
Gitler, Aaron D.