DJ-1 facilitates the interaction between STAT1 and its phosphatase, SHP-1, in brain microglia and astrocytes: A novel anti-inflammatory function of DJ-1
DJ-1 facilitates the interaction between STAT1 and its phosphatase, SHP-1, in brain microglia and astrocytes: A novel anti-inflammatory function of DJ-1
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DOI：
10.1016/j.nbd.2013.08.007
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发表时间：
2013-12-01
影响因子：
6.1
通讯作者：
Joe, Eun-Hye
中科院分区：
文献类型：
--
作者：
Kim, Jong-hyeon;Choi, Dong-joo;Joe, Eun-Hye
帕金森病（PD）是一种由黑质多巴胺能神经元死亡引起的进行性神经退行性运动障碍。重要的是，星形胶质细胞和小胶质细胞功能的改变可能导致PD患者的神经元死亡。在这项研究中，我们发现了一种新的机制，即早发常染色体隐性PD基因DJ-1 （PARK7）通过促进STAT1与其磷酸酶SHP-1 （Src-homology 2-domain containing protein tyrosine phosphatase-1）之间的相互作用，负性调节星形胶质细胞和小胶质细胞的炎症反应。与野生型（WT）小鼠相比，dj -1敲除（KO）小鼠培养的星形胶质细胞和小胶质细胞在干扰素γ (ifn - γ)的作用下，炎症介质的表达和STAT1 （p-STAT1）的磷酸化水平均有所增加。DJ-1缺乏也减弱了ifn - γ诱导的SHP-1与p-STAT1和STAT1的相互作用，分别在ifn - γ处理后1和12小时测量。随后的实验表明，DJ-1直接与SHP-1、p-STAT1和STAT1相互作用。值得注意的是，DJ-1与SHP-1的结合独立于IFN-gamma，而DJ-1与p-STAT1和STAT1的相互作用依赖于IFN-gamma。在脑切片培养中也得到了类似的结果，在KO切片中，ifn - γ诱导的STAT1磷酸化和炎症反应比WT切片强得多。此外，ifn - γ处理诱导KO切片神经元损伤。总的来说，这些发现表明，DJ-1可能作为一种支架蛋白，促进SHP-1与p-STAT1和STAT1的相互作用，从而阻止STAT1广泛和长时间的激活。因此，DJ-1功能的丧失可能通过增强脑炎症而增加PD的风险。爱思唯尔公司版权所有版权所有。
Parkinson's disease (PD) is a progressive neurodegenerative movement disorder caused by the death of dopaminergic neurons in the substantia nigra. Importantly, altered astrocyte and microglial functions could contribute to neuronal death in PD. In this study, we demonstrate a novel mechanism by which DJ-1 (PARK7), an early onset autosomal-recessive PD gene, negatively regulates inflammatory responses of astrocytes and microglia by facilitating the interaction between STAT1 and its phosphatase, SHP-1 (Src-homology 2-domain containing protein tyrosine phosphatase-1). Astrocytes and microglia cultured from DJ-1-knockout (KO) mice exhibited increased expression of inflammatory mediators and phosphorylation levels of STAT1 (p-STAT1) in response to interferon-gamma (IFN-gamma) compared to cells from wild-type (WT) mice. DJ-1 deficiency also attenuated IFN-gamma-induced interactions of SHP-1 with p-STAT1 and STAT1, measured 1 and 12 h after IFN-gamma treatment, respectively. Subsequent experiments showed that DJ-1 directly interacts with SHP-1, p-STAT1, and STAT1. Notably, DJ-1 bound to SHP-1 independently of IFN-gamma, whereas the interactions of DJ-1, with p-STAT1 and STAT1 were dependent on IFN-gamma. Similar results were obtained in brain slice cultures, where IFN-gamma induced much stronger STAT1 phosphorylation and inflammatory responses in KO slices than in WT slices. Moreover, IFN-gamma treatment induced neuronal damage in KO slices. Collectively, these findings suggest that DJ-1 may function as a scaffold protein that facilitates SHP-1 interactions with p-STAT1 and STAT1, thereby preventing extensive and prolonged STAT1 activation. Thus, the loss of DJ-1 function may increase the risk of PD by enhancing brain inflammation. Crown Copyright (C) 2013 Published by Elsevier Inc. All rights reserved.