Reactive Oxygen Species-Mediated DJ-1 Monomerization Modulates Intracellular Trafficking Involving Karyopherin β2
Reactive Oxygen Species-Mediated DJ-1 Monomerization Modulates Intracellular Trafficking Involving Karyopherin β2
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DOI：
10.1128/mcb.00286-14
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发表时间：
2014-08-01
影响因子：
5.3
通讯作者：
Moller, Simon Geir
中科院分区：
文献类型：
--
作者：
Bjorkblom, Benny;Maple-Grodem, Jodi;Moller, Simon Geir
DJ-1突变是隐性早发性帕金森病（PD）的原因。虽然氧化应激和线粒体完整性与PD有关，但神经元退化的原因在很大程度上尚不清楚。DJ-1参与氧化应激介导的反应和线粒体维护;然而，其具体功能仍然模糊。在这里，我们表明，DJ-1表现出神经元的动态细胞内运输，与二聚体/单体的循环调节的氧化环境。我们证明，氧化应激增强野生型细胞溶质DJ-1的单体化，导致核招聘。致病性DJ-1/E163 K变体不能同源二聚化，但在野生型DJ-1异源二聚化后保留在胞质溶胶中。我们发现这种野生型/致病性异二聚体被氧化应激破坏，导致DJ-1/E163 K线粒体易位。我们进一步证明了内源性表达的野生型DJ-1作为单体被导入神经元细胞核，并且核质转运是氧化应激介导的。我们在DJ-1中发现了一种新的脯氨酸-酪氨酸核定位信号（PY-NLS），并且我们发现核单体DJ-1的输入是由与核细胞膜蛋白β 2的氧化应激依赖性相互作用介导的。我们的研究提供的证据表明，氧化应激介导的细胞内运输的DJ-1，介导的动态DJ-1二聚体/单体循环，涉及PD的发病机制。
Mutations in DJ-1 are a cause of recessive, early-onset Parkinson's disease (PD). Although oxidative stress and mitochondrial integrity have been implicated in PD, it is largely unknown why neurons degenerate. DJ-1 is involved in oxidative stress-mediated responses and in mitochondrial maintenance; however, its specific function remains vague. Here we show that DJ-1 exhibits neuronal dynamic intracellular trafficking, with dimeric/monomeric cycling modulated by the oxidative environment. We demonstrate that oxidative stress enhances monomerization of wild-type cytosolic DJ-1, leading to nuclear recruitment. The pathogenic DJ-1/E163K variant is unable to homodimerize but is retained in the cytosol upon wild-type DJ-1 heterodimerization. We found that this wild-type/pathogenic heterodimer is disrupted by oxidative stress, leading to DJ-1/E163K mitochondrial translocation. We further demonstrated that endogenously expressed wild-type DJ-1 is imported into neuronal nuclei as a monomer and that nucleo-cytoplasmic transport is oxidative stress mediated. We identified a novel proline-tyrosine nuclear localization signal (PY-NLS) in DJ-1, and we found that nuclear monomeric DJ-1 import is mediated by an oxidative stress-dependent interaction with karyopherin beta 2. Our study provides evidence that oxidative stress-mediated intracellular trafficking of DJ-1, mediated by dynamic DJ-1 dimeric/monomeric cycling, is implicated in PD pathogenesis.