Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Hum Mol Genet. 2012 Mar 1;21(5):1099-110. doi: 10.1093/hmg/ddr539. Epub 2011 Nov 18.
The spinocerebellar ataxia type 7 (SCA7) gene product, Ataxin-7 (ATXN7), localizes to the nucleus and has been shown to function as a component of the TATA-binding protein-free TAF-containing-SPT3-TAF9-GCN5-acetyltransferase transcription complex, although cytoplasmic localization of ATXN7 in affected neurons of human SCA7 patients has also been detected. Here, we define a physiological function for cytoplasmic ATXN7. Live imaging reveals that the intracellular distribution of ATXN7 dynamically changes and that ATXN7 distribution frequently shifts from the nucleus to the cytoplasm. Immunocytochemistry and immunoprecipitation demonstrate that cytoplasmic ATXN7 associates with microtubules (MTs), and expression of ATXN7 stabilizes MTs against nocodazole treatment, while ATXN7 knockdown enhances MT degradation. Interestingly, normal and mutant ATXN7 similarly associate with and equally stabilize MTs. Taken together, these findings provide a novel physiological function of ATXN7 in the regulation of cytoskeletal dynamics, and suggest that abnormal cytoskeletal regulation may contribute to SCA7 disease pathology.
脊髓小脑共济失调 7 型 (SCA7) 基因产物，共济失调蛋白-7 (ATXN7)，定位于细胞核，并已被证明作为 TATA 结合蛋白游离 TAF 包含 SPT3-TAF9-GCN5-乙酰转移酶转录复合物的一个组成部分发挥作用，尽管在人类 SCA7 患者的受影响神经元中也检测到 ATXN7 的细胞质定位。在这里，我们定义了细胞质 ATXN7 的生理功能。实时成像显示 ATXN7 的细胞内分布动态变化，ATXN7 的分布经常从细胞核转移到细胞质。免疫细胞化学和免疫沉淀表明细胞质 ATXN7 与微管 (MTs) 相关联，并且 ATXN7 的表达稳定 MTs 对抗诺考达唑处理，而 ATXN7 的敲低增强 MT 降解。有趣的是，正常和突变的 ATXN7 同样与 MTs 相关联并同样稳定 MTs。总之，这些发现为 ATXN7 在调节细胞骨架动力学中的新的生理功能提供了依据，并表明异常的细胞骨架调节可能导致 SCA7 疾病病理学。
