Disease-associated mutations affect TIA1 phase separation and aggregation in a proline-dependent manner
Disease-associated mutations affect TIA1 phase separation and aggregation in a proline-dependent manner
复制标题
疾病相关突变以脯氨酸依赖性方式影响 TIA1 相分离和聚集
DOI：
10.1016/j.brainres.2021.147589
复制
发表时间：
2021-08-04
期刊：
影响因子：
2.9
通讯作者：
Luo, Shi-Zhong
中科院分区：
文献类型：
--
作者：
Ding, Xiufang;Gu, Siyu;Luo, Shi-Zhong
T细胞限制性胞内抗原1(TIA1)是一种RNA结合蛋白，是应激颗粒(SGS)的主要成分。TIA1的低复杂结构域(LCD)在通过液-液相分离(LLP)促进SGS组装方面发挥着核心作用。有限合伙人程序的中断与几种疾病有关。最近的研究表明，富含脯氨酸的结构域影响一些蛋白质(如UBQLN2和Tau)的LLP过程。因此，脯氨酸可能调节LLP。TIA1的LCD包含11个脯氨酸残基，几个与Pro相关的突变已被证明可导致肌萎缩侧索硬化症(ALS)和额颞部痴呆(FTD)。在这里，我们证明了TIA1可以在细胞内进行相分离。此外，疾病相关的脯氨酸到亮氨酸(P-L)突变改变了液滴的形态，促进了TIA1向固体样淀粉样纤维的液-固相转变。P-L突变的物理性质的改变改变了TIA1在体内的行为，导致SGS动力学异常，导致ALS病理性包裹体的形成。脯氨酸是调节TIA1 LLP的关键残基。
T-cell restriction intracellular antigen 1 (TIA1) is an RNA-binding protein that is a major component of stress granules (SGs). The low complexity domain (LCD) of TIA1 plays a central role in facilitating SGs assembly through liquid-liquid phase separation (LLPS). Disruption of the LLPS process has been associated with several diseases. It has recently been shown that the proline-rich domain affects the LLPS process of some proteins (such as UBQLN2 and Tau). Thus, proline may regulate LLPS. The LCD of TIA1 contains 11 proline residues, and several proline-related mutations have been shown to cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we demonstrated that TIA1 can undergo phase separation in cells. Additionally, disease-associated proline-to-leucine (P-L) mutations, which altered droplet morphology, facilitated the liquidto-solid phase transition of TIA1 into solid-like amyloid fibrils. The changes in the physical properties of the P-L mutation altered the behavior of TIA1 in vivo and led to abnormal SGs kinetics, resulting in the formation of the pathological inclusions of ALS. Prolines are the key residues for regulating the LLPS of TIA1.