PHLDA1 promotes microglia-mediated neuroinflammation via regulating K63-linked ubiquitination of TRAF6
PHLDA1 promotes microglia-mediated neuroinflammation via regulating K63-linked ubiquitination of TRAF6
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PHLDA1 通过调节 TRAF6 的 K63 泛素化促进小胶质细胞介导的神经炎症
DOI：
10.1016/j.bbi.2020.04.064
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发表时间：
2020-08-01
影响因子：
15.1
通讯作者：
Zhen, Xuechu
中科院分区：
文献类型：
--
作者：
Han, Chaojun;Yan, Pengju;Zhen, Xuechu
小胶质细胞介导的神经炎症在包括帕金森病（PD）在内的神经退行性疾病的进展中起重要作用。Pleckstrin同源样结构域家族A成员1 （PHLDA1）在免疫调节中起重要作用，特别是在toll样受体介导的免疫应答中。在这里，我们探讨了PHLDA1在小胶质细胞介导的炎症和神经元保护中的潜在作用。我们发现PHLDA1的表达在体内或体外的小胶质细胞中对炎症刺激的反应迅速增加。使用腺相关病毒血清型（AAV）敲低PHLDA1可改善mptp诱导的小鼠运动缺陷并抑制神经炎症。为了支持这一体内观察，我们发现lps诱导的促炎基因表达，包括tnf - α、IL-1 β、iNOS和COX-2，在phlda1缺失的小胶质细胞中降低。机制研究表明，在LPS刺激下，PHLDA1在小胶质细胞中的表达增加，导致与TRAF6直接相互作用，并增强其k63连接的泛素化介导的NF-kappa B信号激活。PHLDA1缺乏干扰TRAF6 k63连锁泛素化，抑制小胶质细胞炎症反应。这些发现首次证明PHLDA1是与小胶质细胞介导的多巴胺能神经毒性相关的小胶质细胞功能的重要调节剂。因此，这些数据提供了PHLDA1可能是神经炎症的有效调节剂的第一个证据，PHLDA1可能是治疗神经炎症相关疾病（如PD）的新药物靶点。
Microglia-mediated neuroinflammation plays an important role in the progression of neurodegenerative diseases including Parkinson's disease (PD). Pleckstrin homology-like domain family A member 1 (PHLDA1) plays an important role in immunological regulation, particularly in the Toll-like receptor-mediated immune response. Here, we explored the potential roles of PHLDA1 in microglia-mediated inflammation and neuronal protection. We found that PHLDA1 expression was rapidly increased in response to inflammatory stimuli in microglia cells in vivo or in vitro. Knockdown of PHLDA1 using adeno-associated virus serotype (AAV) ameliorated MPTP-induced motor deficits and inhibited neuroinflammation in mice. In support of this observation in vivo, we found that LPS-induced proinflammatory gene expression, including TNF-alpha, IL-1 beta, iNOS, and COX-2, was decreased in PHLDA1-deficient microglial cells. Mechanistic studies demonstrated that increased expression of PHLDA1, upon LPS stimulation in microglia, led to direct interaction with TRAF6 and enhanced its K63-linked ubiquitinationmediated NF-kappa B signaling activation. PHLDA1 deficiency interfered with TRAF6 K63-linked ubiquitination and inhibited microglial inflammatory responses. These findings reveal the first evidence that PHLDA1 is an important modulator of microglial function that is associated with microglia-mediated dopaminergic neurotoxicity. The data therefore provided the first evidence that PHLDA1 may be a potent modulator for neuroinflammation, and PHLDA1 may be a novel drug target for treatment of neuroinflammation-related diseases such as PD.