Amyotrophic lateral sclerosis-linked FUS/TLS alters stress granule assembly and dynamics.
Amyotrophic lateral sclerosis-linked FUS/TLS alters stress granule assembly and dynamics.
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DOI：
10.1186/1750-1326-8-30
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发表时间：
2013-08-31
影响因子：
15.1
通讯作者：
Bosco DA
中科院分区：
文献类型：
--
作者：
Baron DM;Kaushansky LJ;Ward CL;Sama RR;Chian RJ;Boggio KJ;Quaresma AJ;Nickerson JA;Bosco DA
肌萎缩侧索硬化症（ALS）相关的肉瘤融合/脂肪肉瘤易位（FUS/TLS或FUS）在诱导应激条件下集中在细胞质应激颗粒内。由于在迄今为止报道的大多数应激条件下，只有突变体而不是内源性野生型FUS与应激颗粒相关，因此FUS和应激颗粒之间的关系代表了突变体特异性表型，因此可能在突变体中具有重要意义诱导发病机制。虽然已经很好地建立了muplant-FUS与应激颗粒的关联，但尚未检查突变蛋白对应激颗粒的影响。在这里，我们研究了在氧化应激条件下，muscum-FUS对应激颗粒形成和动力学的影响。我们发现，表达的mukaryo-FUS延迟组装的应力颗粒。然而，一旦形成含有mu-FUS的应激颗粒，与缺乏FUS的应激颗粒相比，它们更动态、更大和更丰富。一旦压力被移除，压力颗粒在表达mukaryo-FUS的细胞中更快地分解。这些效应与muplant-FUS细胞质定位的程度直接相关，这是由蛋白质的核定位信号中的突变诱导的。我们还确定了FUS内的RGG结构域在其与应激颗粒的关联中起着关键作用。虽然有人推测这些RGG结构域内的精氨酸甲基化调节FUS掺入应激颗粒，但我们的结果表明，这种翻译后修饰并不涉及。我们的研究结果表明，muscum-FUS改变了应激颗粒的动力学特性，这与muscum-FUS在应激颗粒组装和细胞应激反应中的毒性获得机制是一致的。
Amyotrophic lateral sclerosis (ALS)-linked fused in sarcoma/translocated in liposarcoma (FUS/TLS or FUS) is concentrated within cytoplasmic stress granules under conditions of induced stress. Since only the mutants, but not the endogenous wild-type FUS, are associated with stress granules under most of the stress conditions reported to date, the relationship between FUS and stress granules represents a mutant-specific phenotype and thus may be of significance in mutant-induced pathogenesis. While the association of mutant-FUS with stress granules is well established, the effect of the mutant protein on stress granules has not been examined. Here we investigated the effect of mutant-FUS on stress granule formation and dynamics under conditions of oxidative stress. We found that expression of mutant-FUS delays the assembly of stress granules. However, once stress granules containing mutant-FUS are formed, they are more dynamic, larger and more abundant compared to stress granules lacking FUS. Once stress is removed, stress granules disassemble more rapidly in cells expressing mutant-FUS. These effects directly correlate with the degree of mutant-FUS cytoplasmic localization, which is induced by mutations in the nuclear localization signal of the protein. We also determine that the RGG domains within FUS play a key role in its association to stress granules. While there has been speculation that arginine methylation within these RGG domains modulates the incorporation of FUS into stress granules, our results demonstrate that this post-translational modification is not involved. Our results indicate that mutant-FUS alters the dynamic properties of stress granules, which is consistent with a gain-of-toxic mechanism for mutant-FUS in stress granule assembly and cellular stress response.
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影响因子：
4.2
作者：
Gal J;Zhang J;Kwinter DM;Zhai J;Jia H;Jia J;Zhu H
通讯作者：
Zhu H
内源性TDP-43而不是FUS，通过G3BP导致应力颗粒组件。
影响因子：
15.1
作者：
Aulas A;Stabile S;Vande Velde C
通讯作者：
Vande Velde C
影响因子：
--
作者：
Andersson MK;Ståhlberg A;Arvidsson Y;Olofsson A;Semb H;Stenman G;Nilsson O;Aman P
通讯作者：
Aman P
影响因子：
3.7
作者：
De Leeuw, Frederic;Zhang, Tong;Gueydan, Cyril
通讯作者：
Gueydan, Cyril
影响因子：
2.9
作者：
GRANT, AJ;LERNER, LM
通讯作者：
LERNER, LM