Knockdown of transactive response DNA-binding protein (TDP-43) downregulates histone deacetylase 6
Knockdown of transactive response DNA-binding protein (TDP-43) downregulates histone deacetylase 6
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DOI：
10.1038/emboj.2009.324
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发表时间：
2010-01-06
期刊：
影响因子：
11.4
通讯作者：
Kahle, Philipp J.
中科院分区：
文献类型：
--
作者：
Fiesel, Fabienne C.;Voigt, Aaron;Kahle, Philipp J.
TDP-43 是一种 RNA/DNA 结合蛋白，参与转录抑制和 mRNA 加工。 TDP-43 内含物是额颞叶痴呆和肌萎缩侧索硬化症的标志。除了 TDP-43 聚集之外，在疾病中还观察到核定位的丧失。为了确定 TDP-43 的相关靶标，我们进行了表达谱分析。因此，在 TDP-43 沉默中发现组蛋白脱乙酰酶 6 (HDAC6) 下调，并在人胚肾 HEK293E 和神经元 SH-SY5Y 细胞的 mRNA 和蛋白质水平上得到证实。这伴随着主要 HDAC6 底物乙酰微管蛋白的积累。 HDAC6 水平通过 TDP-43 的重新表达而恢复，这取决于 RNA 结合和 C 端蛋白质相互作用结构域。此外，TDP-43 与 HDAC6 mRNA 特异性结合，这说明存在直接的功能相互作用。重要的是，TDP-43 敲除果蝇的体内验证证实了 HDAC6 的特异性下调。 HDAC6 对于蛋白质聚集体的形成和降解是必需的。事实上，在 TDP-43 沉默细胞中发现了 HDAC6 依赖性的细胞聚集体形成减少和 PolyQ 扩增的 ataxin-3 的细胞毒性增加。总之，功能性 TDP-43 的丧失会导致 HDAC6 下调，从而可能促进发病机制。 EMBO 杂志 (2010) 29, 209-221。 doi：10.1038/emboj.2009.324； 2009 年 11 月 12 日在线发布
TDP-43 is an RNA/DNA-binding protein implicated in transcriptional repression and mRNA processing. Inclusions of TDP-43 are hallmarks of frontotemporal dementia and amyotrophic lateral sclerosis. Besides aggregation of TDP-43, loss of nuclear localization is observed in disease. To identify relevant targets of TDP-43, we performed expression profiling. Thereby, histone deacetylase 6 (HDAC6) downregulation was discovered on TDP-43 silencing and confirmed at the mRNA and protein level in human embryonic kidney HEK293E and neuronal SH-SY5Y cells. This was accompanied by accumulation of the major HDAC6 substrate, acetyl-tubulin. HDAC6 levels were restored by re-expression of TDP-43, dependent on RNA binding and the C-terminal protein interaction domains. Moreover, TDP-43 bound specifically to HDAC6 mRNA arguing for a direct functional interaction. Importantly, in vivo validation in TDP-43 knockout Drosophila melanogaster confirmed the specific downregulation of HDAC6. HDAC6 is necessary for protein aggregate formation and degradation. Indeed, HDAC6-dependent reduction of cellular aggregate formation and increased cytotoxicity of polyQ-expanded ataxin-3 were found in TDP-43 silenced cells. In conclusion, loss of functional TDP-43 causes HDAC6 downregulation and might thereby contribute to pathogenesis. The EMBO Journal (2010) 29, 209-221. doi: 10.1038/emboj.2009.324; Published online 12 November 2009