DJ-1 transcriptionally up-regulates the human tyrosine hydroxylase by inhibiting the sumoylation of pyrimidine tract-binding protein-associated splicing factor
DJ-1 transcriptionally up-regulates the human tyrosine hydroxylase by inhibiting the sumoylation of pyrimidine tract-binding protein-associated splicing factor
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DOI：
10.1074/jbc.m601935200
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发表时间：
2006-07-28
影响因子：
4.8
通讯作者：
Xu, Jin
中科院分区：
文献类型：
--
作者：
Zhong, Nan;Kim, Christina Y.;Xu, Jin
DJ-1功能丧失突变导致家族性帕金森病(PD)的一个子集。然而，DJ-1失活导致多巴胺能通路选择性易损性的机制尚不清楚。此前，我们已报道DJ-1是一种神经保护性转录共激活因子，与转录共抑制因子嘧啶结合蛋白相关剪接因子(PSF)相互作用。在这里，我们证明了DJ-1和PSF结合和调节人酪氨酸羟化酶(TH)启动子。小干扰RNA使DJ-1失活，导致人多巴胺能细胞系TH表达和L多巴生成量下降。与其作为转录调节因子的作用一致，DJ-1特异性地抑制全球相扑-1的修饰。携带致病性DJ-1突变的患者的淋巴母细胞中积累了包括PSF在内的高分子量求和蛋白物种。DJ-1通过抑制PSF的总甲基化和阻止其依赖总甲基化的组蛋白脱乙酰基酶1的募集来上调TH的表达。此外，DJ-1的siRNA沉默降低了TH启动子结合的组蛋白的乙酰化，组蛋白脱乙酰酶抑制剂恢复了DJ-1 siRNA诱导的TH的抑制。因此，我们的结果提示DJ-1是一种蛋白质和甲基化的调节剂，并直接将DJ-1的表达缺失和转录功能障碍与多巴胺合成障碍联系起来。
Loss-of-function mutations in DJ-1 cause a subset of familial Parkinson disease (PD). However, the mechanism underlying the selective vulnerability in dopaminergic pathway due to the inactivation of DJ-1 is unclear. Previously, we have reported that DJ-1 is a neuroprotective transcriptional coactivator interacting with the transcriptional co-repressor pyrimidine tract-binding protein-associated splicing factor (PSF). Here we show that DJ-1 and PSF bind and regulate the human tyrosine hydroxylase (TH) promoter. Inactivation of DJ-1 by small interference RNA ( siRNA) results in decreased TH expression and L-DOPA production in human dopaminergic cell lines. Consistent with its role as a transcriptional regulator, DJ-1 specifically suppresses the global SUMO-1 modification. High molecular weight sumoylated protein species, including PSF, accumulate in the lymphoblast cells from the patients carrying pathogenic DJ-1 mutations. DJ-1 elevates the TH expression by inhibiting the sumoylation of PSF and preventing its sumoylation-dependent recruitment of histone deacetylase 1. Furthermore, siRNA silencing of DJ-1 decreases the acetylation of TH promoter-bound histones, and histone deacetylase inhibitors restore the DJ-1 siRNA-induced repression of TH. Therefore, our results suggest DJ-1 as a regulator of protein sumoylation and directly link the loss of DJ-1 expression and transcriptional dysfunction to impaired dopamine synthesis.