Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery.
Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery.
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DOI：
10.1021/pr901076y
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发表时间：
2010-02-05
影响因子：
4.4
通讯作者：
Taylor, J. Paul
中科院分区：
文献类型：
--
作者：
Freibaum, Brian D.;Chitta, Raghu K.;High, Anthony A.;Taylor, J. Paul
TDP-43是异质核核糖核蛋白（hnRNP）蛋白家族的高度保守和普遍表达的成员。最近，TDP-43被证明是肌萎缩侧索硬化症（ALS）、tau蛋白阴性额颞叶变性（FTLD）和包涵体肌病的大多数病例的泛素化包涵体特征中的主要疾病蛋白。在这些疾病中，TDP-43从其主要的核位置重新分布到泛素阳性的细胞质病灶。TDP-43驱动病理生理学的程度尚不清楚，但在ALS和FTLD-U家族形式中TDP-43突变的鉴定表明该蛋白在发病机制中的重要作用。关于TDP-43的功能知之甚少，以前只鉴定了少数TDP-43相互作用蛋白，这使得进一步深入了解TDP-43的正常和病理功能变得困难。在这里，我们表明，通过全球蛋白质组学的方法，TDP-43与调节RNA代谢的蛋白质有广泛的相互作用。发现与TDP-43的一些相互作用依赖于RNA结合，而其他相互作用是RNA独立的。TDP-43中的致病突变（A315 T和M337 V）不会改变其相互作用谱。TDP-43相互作用蛋白主要聚集成两个不同的相互作用网络，核/剪接簇和细胞质/翻译簇，强烈表明TDP-43在RNA代谢中具有多种作用，并在细胞核和细胞质中发挥作用。最后，我们发现了许多TDP-43的相互作用，是已知的组成部分的压力颗粒，事实上，我们发现，TDP-43也被招募到压力颗粒。
TDP-43 is a highly conserved and ubiquitously expressed member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family of proteins. Recently, TDP-43 was shown to be a major disease protein in the ubiquitinated inclusions characteristic of most cases of amyotrophic lateral sclerosis (ALS), tau-negative frontotemporal lobar degeneration (FTLD), and inclusion body myopathy. In these diseases, TDP-43 is redistributed from its predominantly nuclear location to ubiquitin-positive, cytoplasmic foci. The extent to which TDP-43 drives pathophysiology is unknown, but the identification of mutations in TDP-43 in familial forms of ALS and FTLD-U suggests an important role for this protein in pathogenesis. Little is known about TDP-43 function and only a few TDP-43 interacting proteins have been previously identified, which makes further insight into both the normal and pathological functions of TDP-43 difficult. Here we show, via a global proteomic approach, that TDP-43 has extensive interaction with proteins that regulate RNA metabolism. Some interactions with TDP-43 were found to be dependent on RNA-binding, whereas other interactions are RNA-independent. Disease-causing mutations in TDP-43 (A315T and M337V) do not alter its interaction profile. TDP-43 interacting proteins largely cluster into two distinct interaction networks, a nuclear/splicing cluster and a cytoplasmic/translation cluster, strongly suggesting that TDP-43 has multiple roles in RNA metabolism and functions in both the nucleus and the cytoplasm. Finally, we found numerous TDP-43 interactors that are known components of stress granules and, indeed, we find that TDP-43 is also recruited to stress granules.
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影响因子：
64.5
作者：
Cooper TA;Wan L;Dreyfuss G
通讯作者：
Dreyfuss G
影响因子：
64.5
作者：
LEFEBVRE, S;BURGLEN, L;MELKI, J
通讯作者：
MELKI, J
影响因子：
14.9
作者：
Jensen LJ;Kuhn M;Stark M;Chaffron S;Creevey C;Muller J;Doerks T;Julien P;Roth A;Simonovic M;Bork P;von Mering C
通讯作者：
von Mering C
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：
4
作者：
Ayala, Youhna M.;Zago, Paola;Baralle, Francisco E.
通讯作者：
Baralle, Francisco E.