Autophagy regulates MAVS signaling activation in a phosphorylation-dependent manner in microglia
Autophagy regulates MAVS signaling activation in a phosphorylation-dependent manner in microglia
复制标题
小胶质细胞中自噬以磷酸化依赖性方式调节 MAVS 信号激活。
DOI：
10.1038/cdd.2016.121
复制
发表时间：
2017-02-01
影响因子：
12.4
通讯作者：
Yuan, Zengqiang
中科院分区：
文献类型：
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作者：
Cheng, Jinbo;Liao, Yajin;Yuan, Zengqiang
线粒体抗病毒信号（MAVS）蛋白在抗病毒免疫和自身免疫中具有重要作用。然而，这种信号通路的病理生理作用，特别是在大脑中，仍然是难以捉摸的。在这里，我们证明了MAVS信号的存在并介导了大脑中多聚（I: C）诱导的炎症。随着MAVS信号的激活，诱导了自噬激活。自噬通过LC3直接结合MAVS的LIR基序Y (9) xxI（12）负向调节MAVS的活性。我们还发现c-Abl激酶磷酸化MAVS并调节其与LC3的相互作用。有趣的是，MAVS的酪氨酸磷酸化是下游信号激活所必需的。重要的是，体内数据显示，MAVS或c-Abl的缺乏可阻止mptp诱导的小胶质细胞激活和多巴胺能神经元丢失。总之，我们的研究结果揭示了神经系统中mavs依赖性小胶质细胞激活调控的分子机制，从而为治疗小胶质细胞驱动的炎症性脑疾病提供了潜在的靶点。
Mitochondrial antiviral signaling (MAVS) protein has an important role in antiviral immunity and autoimmunity. However, the pathophysiological role of this signaling pathway, especially in the brain, remains elusive. Here we demonstrated that MAVS signaling existed and mediated poly (I: C)-induced inflammation in the brain. Along with the MAVS signaling activation, there was an induction of autophagic activation. Autophagy negatively regulated the activity of MAVS through direct binding of LC3 to the LIR motif Y (9) xxI (12) of MAVS. We also found that c-Abl kinase phosphorylated MAVS and regulated its interaction with LC3. Interestingly, tyrosine phosphorylation of MAVS was required for downstream signaling activation. Importantly, in vivo data showed that the deficiency of MAVS or c-Abl prevented MPTP-induced microglial activation and dopaminergic neuron loss. Together, our findings reveal the molecular mechanisms underlying the regulation of MAVS-dependent microglial activation in the nervous system, thus providing a potential target for the treatment of microglia-driven inflammatory brain diseases.