Profilin 1 Associates with Stress Granules and ALS-Linked Mutations Alter Stress Granule Dynamics
Profilin 1 Associates with Stress Granules and ALS-Linked Mutations Alter Stress Granule Dynamics
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DOI：
10.1523/jneurosci.0543-14.2014
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发表时间：
2014-06-11
影响因子：
5.3
通讯作者：
Gitler, Aaron D.
中科院分区：
文献类型：
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作者：
Figley, Matthew D.;Bieri, Gregor;Gitler, Aaron D.
编码Profilin 1的PFN1基因突变是家族性肌萎缩侧索硬化症(ALS)的罕见原因。Profilin 1是一种研究很好的肌动蛋白结合蛋白，但PFN1突变如何导致ALS尚不清楚。萌芽酵母，酿酒酵母，有一个PFN1同源基因。我们在酵母中表达了肌萎缩侧索硬化症连锁的Profilin 1突变蛋白，显示出蛋白稳定性的丧失和Profilin突变细胞的生长未能恢复，没有表现出功能获得毒性。该模型提供了简单和快速的新的ALS连锁的PFN1变异体的筛选。为了深入了解Profilin 1的潜在新作用，我们对缺乏Profilin的酵母细胞(Pfy1 Delta)进行了无偏见的全基因组合成致死筛选。出乎意料的是，包括pbp1 Delta在内的几个应激颗粒和处理身体基因的缺失被发现是与pfy1 Delta合成致命的。人类PBP1的同源基因ATXN2的突变是已知的ALS遗传风险因素，而ataxin 2是哺乳动物细胞中的一种应激颗粒成分。考虑到这种遗传交互作用和最近将应激颗粒动力学与ALS发病机制联系起来的证据，我们假设Profilin 1也可能与应激颗粒有关。在这里，我们报道了profilin 1及其相关蛋白profilin 2是小鼠原代皮层神经元和人类细胞系中新的应激颗粒相关蛋白，profilin 1的突变改变了应激颗粒的动力学，为应激颗粒在ALS发病机制中的潜在作用提供了进一步的证据。
Mutations in the PFN1 gene encoding profilin 1 are a rare cause of familial amyotrophic lateral sclerosis (ALS). Profilin 1 is a well studied actin-binding protein but how PFN1 mutations cause ALS is unknown. The budding yeast, Saccharomyces cerevisiae, has one PFN1 ortholog. We expressed the ALS-linked profilin 1 mutant proteins in yeast, demonstrating a loss of protein stability and failure to restore growth to profilin mutant cells, without exhibiting gain-of-function toxicity. This model provides for simple and rapid screening of novel ALS-linked PFN1 variants. To gain insight into potential novel roles for profilin 1, we performed an unbiased, genome-wide synthetic lethal screen with yeast cells lacking profilin (pfy1 Delta). Unexpectedly, deletion of several stress granule and processing body genes, including pbp1 Delta, were found to be synthetic lethal with pfy1 Delta. Mutations in ATXN2, the human ortholog of PBP1, are a known ALS genetic risk factor and ataxin 2 is a stress granule component in mammalian cells. Given this genetic interaction and recent evidence linking stress granule dynamics to ALS pathogenesis, we hypothesized that profilin 1 might also associate with stress granules. Here we report that profilin 1 and related protein profilin 2 are novel stress granule-associated proteins in mouse primary cortical neurons and in human cell lines and that ALS-linked mutations in profilin 1 alter stress granule dynamics, providing further evidence for the potential role of stress granules in ALS pathogenesis.