Subcellular expression of autoimmune regulator is organized in a spatiotemporal manner
Subcellular expression of autoimmune regulator is organized in a spatiotemporal manner
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DOI：
10.1074/jbc.m400702200
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发表时间：
2004-08-06
影响因子：
4.8
通讯作者：
Matsumoto, M
中科院分区：
文献类型：
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作者：
Akiyoshi, H;Hatakeyama, S;Matsumoto, M
自身免疫调节因子(AIRE)以单基因方式导致器官特异性自身免疫性疾病的发生。罕见和低水平的组织表达，加上缺乏AIRE表达的细胞系，阻碍了对AIRE分子动力学的详细分析。在这里，我们建立了稳定转染AIRE的细胞系，并研究了其亚细胞表达的调控机制。我们发现AIRE核小体的形成依赖于细胞周期。生化分级显示，有相当大比例的AIRE与核基质有关，核基质引导染色质的功能结构域为基因调控提供位点。当蛋白酶体被抑制时，AIRE NBS在细胞质中的表达增加，伴随而来的是表达减少，这表明AIRE的亚细胞靶向性受泛素-蛋白酶体途径的调节。我们还发现，AIRE NBS与早幼粒细胞白血病基因产物竞争cAMP反应元件结合蛋白结合蛋白/p300，这是一种常见的转录共激活因子。这些结果表明，AIRE在细胞内的转录调控活动是以时空方式控制和组织的。
Autoimmune regulator ( AIRE) is responsible for the development of organ-specific autoimmune disease in a monogenic fashion. Rare and low levels of tissue expression together with the lack of AIRE-expressing cell lines have hampered a detailed analysis of the molecular dynamics of AIRE. Here we have established cell lines stably transfected with AIRE and studied the regulatory mechanisms for its subcellular expression. We found that nuclear body ( NB) formation by AIRE was dependent on the cell cycle. Biochemical fractionation revealed that a significant proportion of AIRE is associated with the nuclear matrix, which directs the functional domains of chromatin to provide sites for gene regulation. Upon proteasome inhibition, AIRE NBs were increased with concomitant reduced expression in the cytoplasm, suggesting that subcellular targeting of AIRE is regulated by a ubiquitin-proteasome pathway. We also found that AIRE NBs compete for cAMP-response element-binding protein-binding protein/p300, a common coactivator of transcription, with the promyelocytic leukemia gene product. These results suggest that the transcriptional regulating activities of AIRE within a cell are controlled and organized in a spatiotemporal manner.