Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076, Tübingen, Germany.
German Center for Neurodegenerative Diseases (DZNE), 72076, Tübingen, Germany.
Nat Commun. 2022 Mar 9;13(1):1223. doi: 10.1038/s41467-022-28822-7.
Trans-activation response DNA-binding protein of 43 kDa (TDP-43) regulates RNA processing and forms neuropathological aggregates in patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Investigating TDP-43 post-translational modifications, we discovered that K84 acetylation reduced nuclear import whereas K136 acetylation impaired RNA binding and splicing capabilities of TDP-43. Such failure of RNA interaction triggered TDP-43 phase separation mediated by the C-terminal low complexity domain, leading to the formation of insoluble aggregates with pathologically phosphorylated and ubiquitinated TDP-43. Introduction of acetyl-lysine at the identified sites via amber suppression confirmed the results from site-directed mutagenesis. K84-acetylated TDP-43 showed cytoplasmic mislocalization, and the aggregation propensity of K136-acetylated TDP-43 was confirmed. We generated antibodies selective for TDP-43 acetylated at these lysines, and found that sirtuin-1 can potently deacetylate K136-acetylated TDP-43 and reduce its aggregation propensity. Thus, distinct lysine acetylations modulate nuclear import, RNA binding and phase separation of TDP-43, suggesting regulatory mechanisms for TDP-43 pathogenesis.
43kDa 的反式激活反应 DNA 结合蛋白 (TDP-43) 调节 RNA 加工，并在肌萎缩侧索硬化症和额颞叶变性患者中形成神经病理学聚集物。研究 TDP-43 的翻译后修饰时，我们发现 K84 乙酰化降低了核输入，而 K136 乙酰化则损害了 TDP-43 的 RNA 结合和剪接能力。这种 RNA 相互作用的失败触发了 TDP-43 由 C 端低复杂度结构域介导的相分离，导致病理性磷酸化和泛素化 TDP-43 的不溶性聚集物形成。通过琥珀酰抑制在鉴定的位点引入乙酰化赖氨酸，证实了定点突变的结果。K84 乙酰化的 TDP-43 显示细胞质定位错误，并且 K136 乙酰化的 TDP-43 的聚集倾向得到了证实。我们生成了针对这些赖氨酸乙酰化的 TDP-43 的特异性抗体，并发现 Sirtuin-1 可以有效地去乙酰化 K136 乙酰化的 TDP-43 并降低其聚集倾向。因此，不同的赖氨酸乙酰化调节 TDP-43 的核输入、RNA 结合和相分离，提示 TDP-43 发病机制的调节机制。
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