cAMP Signaling of Adenylate Cyclase Toxin Blocks the Oxidative Burst of Neutrophils through Epac-Mediated Inhibition of Phospholipase C Activity
cAMP Signaling of Adenylate Cyclase Toxin Blocks the Oxidative Burst of Neutrophils through Epac-Mediated Inhibition of Phospholipase C Activity
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DOI：
10.4049/jimmunol.1601309
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发表时间：
2017-02-01
影响因子：
4.4
通讯作者：
Sebo, Peter
中科院分区：
文献类型：
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作者：
Cerny, Ondrej;Anderson, Karen E.;Sebo, Peter
腺苷酸环化酶毒素溶血素（CyaA）在百日咳病原菌百日咳的免疫逃避和毒力中起关键作用。CyaA穿透表达补体受体3的吞噬细胞，并通过催化胞质ATP向关键第二信使分子cAMP的不受调节的转化来消除其杀菌能力。我们发现CyaA产生的cAMP信号传导通过两种会聚机制阻断中性粒细胞的氧化爆发能力。一个涉及cAMP/蛋白激酶A介导的含磷酸酶-1（SHP-1）的Src同源区2结构域的活化，并限制组装NADPH氧化酶复合物所需的MAPK ERK和p38的活化。同时，由cAMP（Epac）直接激活的交换蛋白的激活通过一种未知的机制引起磷脂酶C的抑制。事实上，通过细胞可渗透的类似物8-（4-氯苯硫基）-2 '-O-甲基腺苷-3'，5 '-环一磷酸对Epac的选择性激活抵消了通过2，4，6-三甲基-N43-（三氟甲基）苯基苯磺酰胺对磷脂酶C的直接激活。因此，通过抑制蛋白激酶C活化脂质二酰基甘油的产生，cAMP/Epac信号传导阻断氧化爆发触发的会聚途径的瓶颈步骤。因此，通过CyaA产生的cAMP信号传导对中性粒细胞膜组成的操纵使B成为可能。百日咳以逃避由中性粒细胞介导的活性氧类杀死细菌的关键先天宿主防御机制。
The adenylate cyclase toxin-hemolysin (CyaA) plays a key role in immune evasion and virulence of the whooping cough agent Bordetella pertussis. CyaA penetrates the complement receptor 3 expressing phagocytes and ablates their bactericidal capacities by catalyzing unregulated conversion of cytosolic ATP to the key second messenger molecule cAMP. We show that signaling of CyaA-generated cAMP blocks the oxidative burst capacity of neutrophils by two converging mechanisms. One involves cAMP/ protein kinase A mediated activation of the Src homology region 2 domain containing phosphatase-1 (SHP-1) and limits the activation of MAPK ERK and p38 that are required for assembly of the NADPH oxidase complex. In parallel, activation of the exchange protein directly activated by cAMP (Epac) provokes inhibition of the phospholipase C by an as yet unknown mechanism. Indeed, selective activation of Epac by the cell-permeable analog 8-(4-chlorophenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate counteracted the direct activation of phospholipase C by 2,4,6-trimethyl-N43-(trifluoromethyl)phenylbenzenesulfonamide. Hence, by inhibiting production of the protein kinase C activating lipid, diacylglycerol, cAMP/Epac signaling blocks the bottleneck step of the converging pathways of oxidative burst triggering. Manipulation of neutrophil membrane composition by CyaA-produced signaling of cAMP thus enables B. pertussis to evade the key innate host defense mechanism of reactive oxygen species mediated killing of bacteria by neutrophils.