Tar DNA binding protein-43 (TDP-43) associates with stress granules: analysis of cultured cells and pathological brain tissue.
Tar DNA binding protein-43 (TDP-43) associates with stress granules: analysis of cultured cells and pathological brain tissue.
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DOI：
10.1371/journal.pone.0013250
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发表时间：
2010-10-11
期刊：
影响因子：
3.7
通讯作者：
Wolozin B
中科院分区：
文献类型：
--
作者：
Liu-Yesucevitz L;Bilgutay A;Zhang YJ;Vanderweyde T;Citro A;Mehta T;Zaarur N;McKee A;Bowser R;Sherman M;Petrucelli L;Wolozin B
TAR DNA结合蛋白43（TDP - 43）是额颞叶变性（FTLD - U）和肌萎缩侧索硬化症（ALS）许多病例中包涵体的主要成分。TDP - 43主要位于细胞核中，但在ALS和FTLD - U中枢神经系统的病变区域，TDP - 43被异常加工并形成细胞质包涵体。调控TDP - 43包涵体形成的机制了解甚少。越来越多的证据表明，TDP - 43通过与已知与RNA颗粒相关的mRNA结合蛋白相互作用来调节mRNA代谢。在此我们表明，在细胞培养中TDP - 43可被诱导形成包涵体，并且大多数TDP - 43包涵体与应激颗粒（SGs）共定位。应激颗粒是由蛋白质 - RNA混合复合物组成的细胞质RNA颗粒。在应激条件下，应激颗粒由类朊蛋白（如TIA - 1）的可逆聚集产生，以调节mRNA代谢和蛋白质翻译。我们还表明，TDP - 43中与疾病相关的突变会增加其在应激刺激下包涵体的形成。生化研究表明，TDP - 43包涵体形成的增加与TDP - 43去污剂不溶性复合物的积累有关。TDP - 43通过直接的蛋白质 - 蛋白质相互作用以及RNA依赖性相互作用与应激颗粒蛋白（如TIA - 1）相互作用而与应激颗粒相关联。调节应激颗粒形成的信号通路也调节TDP - 43包涵体的形成。我们观察到，用抑制或逆转应激颗粒形成的翻译抑制剂处理可抑制由野生型或突变型TDP - 43介导的包涵体形成。最后，利用苏丹黑淬灭内源性自发荧光，我们还证明病理中枢神经系统组织中TDP - 43阳性包涵体与应激颗粒的多种蛋白质标记物（包括TIA - 1和eIF3）共定位。这些数据为越来越多的证据（即TDP - 43参与应激颗粒通路）提供了支持。
Tar DNA Binding Protein-43 (TDP-43) is a principle component of inclusions in many cases of frontotemporal lobar degeneration (FTLD-U) and amyotrophic lateral sclerosis (ALS). TDP-43 resides predominantly in the nucleus, but in affected areas of ALS and FTLD-U central nervous system, TDP-43 is aberrantly processed and forms cytoplasmic inclusions. The mechanisms governing TDP-43 inclusion formation are poorly understood. Increasing evidence indicates that TDP-43 regulates mRNA metabolism by interacting with mRNA binding proteins that are known to associate with RNA granules. Here we show that TDP-43 can be induced to form inclusions in cell culture and that most TDP-43 inclusions co-localize with SGs. SGs are cytoplasmic RNA granules that consist of mixed protein - RNA complexes. Under stressful conditions SGs are generated by the reversible aggregation of prion-like proteins, such as TIA-1, to regulate mRNA metabolism and protein translation. We also show that disease-linked mutations in TDP-43 increased TDP-43 inclusion formation in response to stressful stimuli. Biochemical studies demonstrated that the increased TDP-43 inclusion formation is associated with accumulation of TDP-43 detergent insoluble complexes. TDP-43 associates with SG by interacting with SG proteins, such as TIA-1, via direct protein-protein interactions, as well as RNA-dependent interactions. The signaling pathway that regulates SGs formation also modulates TDP-43 inclusion formation. We observed that inclusion formation mediated by WT or mutant TDP-43 can be suppressed by treatment with translational inhibitors that suppress or reverse SG formation. Finally, using Sudan black to quench endogenous autofluorescence, we also demonstrate that TDP-43 positive-inclusions in pathological CNS tissue co-localize with multiple protein markers of stress granules, including TIA-1 and eIF3. These data provide support for accumulating evidence that TDP-43 participates in the SG pathway.
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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：
16.2
作者：
Barbee, Scott A.;Estes, Patricia S.;Ramaswami, Mani
通讯作者：
Ramaswami, Mani
影响因子：
4.8
作者：
Johnson, Brian S.;Snead, David;Gitler, Aaron D.
通讯作者：
Gitler, Aaron D.
影响因子：
12.7
作者：
Brandmeir, Nicholas J.;Geser, Felix;Trojanowski, John Q.
通讯作者：
Trojanowski, John Q.
影响因子：
6
作者：
Cairns, Nigel J.;Neumann, Manuela;Mackenzie, Ian R. A.
通讯作者：
Mackenzie, Ian R. A.