cAMP signalling of Bordetella adenylate cyclase toxin through the SHP-1 phosphatase activates the BimEL-Bax pro-apoptotic cascade in phagocytes
cAMP signalling of Bordetella adenylate cyclase toxin through the SHP-1 phosphatase activates the BimEL-Bax pro-apoptotic cascade in phagocytes
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DOI：
10.1111/cmi.12519
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发表时间：
2016-03-01
影响因子：
3.4
通讯作者：
Sebo, Peter
中科院分区：
文献类型：
--
作者：
Ahmad, Jawid Nazir;Cerny, Ondrej;Sebo, Peter
腺苷酸环化酶毒素溶血素（CyaA， ACT或AC-Hly）在百日咳杆菌的毒力中起关键作用。CyaA穿透表达补体受体3 （（M2）整合素CD11b/CD18）的骨髓细胞，通过催化胞质ATP向关键信号分子腺苷3′，5′-环磷酸腺苷（cAMP）的无调节转化，破坏中性粒细胞和巨噬细胞的杀菌能力。我们发现，cyaa产生的cAMP劫持信号通过一种未知的机制，劫持酪氨酸磷酸酶SHP-1的活性，并激活促凋亡的bmel - bax级联反应。人THP-1巨噬细胞在暴露于低CyaA浓度（如20ngml(-1)） 10min内发生线粒体超极化，并伴有BimEL的积累和促凋亡因子Bax与线粒体的关联。BimEL的积累需要cAMP/蛋白激酶A信号传导，依赖于SHP-1活性，并被选择性地抑制在小干扰RNA敲除SHP-1而不是SHP-2磷酸酶。此外，cyaa产生的cAMP信号传导抑制AKT/蛋白激酶B促生存级联，增强FoxO3a转录因子的活性，诱导Bim转录。FoxO3a激活与SHP-1劫持的协同作用使该毒素能够迅速触发BimEL的持续积累，从而激活巨噬细胞的促凋亡程序并破坏宿主的先天免疫。
The adenylate cyclase toxin-hemolysin (CyaA, ACT or AC-Hly) plays a key role in virulence of Bordetella pertussis. CyaA penetrates myeloid cells expressing the complement receptor 3 ((M2) integrin CD11b/CD18) and subverts bactericidal capacities of neutrophils and macrophages by catalysing unregulated conversion of cytosolic ATP to the key signalling molecule adenosine 3',5'-cyclic monophosphate (cAMP). We show that the signalling of CyaA-produced cAMP hijacks, by an as yet unknown mechanism, the activity of the tyrosine phosphatase SHP-1 and activates the pro-apoptotic BimEL-Bax cascade. Mitochondrial hyperpolarization occurred in human THP-1 macrophages within 10min of exposure to low CyaA concentrations (e.g. 20ngml(-1)) and was accompanied by accumulation of BimEL and association of the pro-apoptotic factor Bax with mitochondria. BimEL accumulation required cAMP/protein kinase A signalling, depended on SHP-1 activity and was selectively inhibited upon small interfering RNA knockdown of SHP-1 but not of the SHP-2 phosphatase. Moreover, signalling of CyaA-produced cAMP inhibited the AKT/protein kinase B pro-survival cascade, enhancing activity of the FoxO3a transcription factor and inducing Bim transcription. Synergy of FoxO3a activation with SHP-1 hijacking thus enables the toxin to rapidly trigger a persistent accumulation of BimEL, thereby activating the pro-apoptotic programme of macrophages and subverting the innate immunity of the host.