Bid-Induced Release of AIF/EndoG from Mitochondria Causes Apoptosis of Macrophages during Infection with Leptospira interrogans.
Bid-Induced Release of AIF/EndoG from Mitochondria Causes Apoptosis of Macrophages during Infection with Leptospira interrogans.
复制标题
在问号钩端螺旋体感染期间，Bid 诱导的 AIF/EndoG 从线粒体中释放导致巨噬细胞凋亡。
DOI：
10.3389/fcimb.2017.00471
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发表时间：
2017
影响因子：
5.7
通讯作者：
Yan J
中科院分区：
文献类型：
--
作者：
Hu WL;Dong HY;Li Y;Ojcius DM;Li SJ;Yan J
钩端螺旋体病是由致病性钩端螺旋体引起的一种全球性人畜共患传染病。钩端螺旋体通过Fas/FasL-caspase-8/3途径诱导巨噬细胞凋亡，对病原体在宿主体内的存活和增殖起重要作用。虽然，释放线粒体凋亡诱导因子（AIF）和内切核酸酶G（EndoG）在钩端螺旋体感染的巨噬细胞已被描述，连接半胱天冬酶和与宿主细胞凋亡相关的机制尚未确定。在这里，我们证明了钩端螺旋体感染诱导细胞凋亡，通过线粒体损伤的巨噬细胞。凋亡是由线粒体释放和核转位的AIF和/或EndoG，导致核DNA片段化。然而，与cytC-caspase-9/3通路相关的cytC-caspase-9/3通路未被激活。接下来，我们发现AIF和/或EndoG的释放和易位之前是BH 3相互作用结构域死亡激动剂（Bid）的激活。此外，我们的数据表明，caspase-8在感染过程中被激活，并引起Bid的激活。同时，感染引起的高活性氧（ROS）引起Akt去磷酸化，从而激活Bid。总之，Bid介导的AIF和/或EndoG的线粒体释放以及随后的核转位是钩端螺旋体诱导的巨噬细胞凋亡的主要机制，并且该过程受到胱天蛋白酶-8和ROS-Akt信号通路的调节。
Leptospirosis is a global zoonotic infectious disease caused by pathogenic Leptospira species. Leptospire-induced macrophage apoptosis through the Fas/FasL-caspase-8/3 pathway plays an important role in the survival and proliferation of the pathogen in hosts. Although, the release of mitochondrial apoptosis-inducing factor (AIF) and endonuclease G (EndoG) in leptospire-infected macrophages has been described, the mechanisms linking caspase and mitochondrion-related host-cell apoptosis has not been determined. Here, we demonstrated that leptospire-infection induced apoptosis through mitochondrial damages in macrophages. Apoptosis was caused by the mitochondrial release and nuclear translocation of AIF and/or EndoG, leading to nuclear DNA fragmentation. However, the mitochondrion-related CytC-caspase-9/3 pathway was not activated. Next, we found that the release and translocation of AIF and/or EndoG was preceded by the activation of the BH3-interacting domain death agonist (Bid). Furthermore, our data demonstrated that caspase-8 was activated during the infection and caused the activation of Bid. Meanwhile, high reactive oxygen species (ROS) trigged by the infection caused the dephosphorylation of Akt, which also activated Bid. In conclusion, Bid-mediated mitochondrial release of AIF and/or EndoG followed by nuclear translocation is a major mechanism of leptospire- induced apoptosis in macrophages, and this process is modulated by both caspase-8 and ROS-Akt signal pathways.