NADPH oxidase-derived H2O2 subverts pathogen signaling by oxidative phosphotyrosine conversion to PB-DOPA
NADPH oxidase-derived H2O2 subverts pathogen signaling by oxidative phosphotyrosine conversion to PB-DOPA
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DOI：
10.1073/pnas.1605443113
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发表时间：
2016-09-13
影响因子：
11.1
通讯作者：
Knaus, Ulla G.
中科院分区：
文献类型：
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作者：
Alvarez, Luis A.;Kovacic, Lidija;Knaus, Ulla G.
加强宿主免疫系统以充分利用其作为抗菌防御的潜力对于对抗抗生素耐药性至关重要。在双向宿主-病原体串扰期间释放的化学化合物遵循感知-响应范例，可以充当保护介质。一个有效的，可扩散的信使是过氧化氢（H2 O2），但其对细胞外病原体的影响是未知的。在这里，我们表明，H2 O2，由主机上释放的病原体接触，颠覆了酪氨酸信号网络的一些细菌习惯于低氧环境。这种防御机制使用具有过氧化物酶样活性的含血红素的细菌酶来促进磷酸酪氨酸（p-Tyr）氧化。细菌内反应通过酪氨酸自由基中间体将对-Tyr转化为蛋白质结合的多巴（PB-DOPA），从而改变抗氧化防御并使参与多糖生物合成和代谢的酶失活。多巴修饰对细菌信号传导的破坏揭示了一种削弱细菌适应性的感染遏制策略，并可能成为抗病力方法的蓝图。
Strengthening the host immune system to fully exploit its potential as antimicrobial defense is vital in countering antibiotic resistance. Chemical compounds released during bidirectional host-pathogen cross-talk, which follows a sensing-response paradigm, can serve as protective mediators. A potent, diffusible messenger is hydrogen peroxide (H2O2), but its consequences on extracellular pathogens are unknown. Here we show that H2O2, released by the host on pathogen contact, subverts the tyrosine signaling network of a number of bacteria accustomed to low-oxygen environments. This defense mechanism uses heme-containing bacterial enzymes with peroxidase-like activity to facilitate phosphotyrosine (p-Tyr) oxidation. An intrabacterial reaction converts p-Tyr to protein-bound dopa (PB-DOPA) via a tyrosinyl radical intermediate, thereby altering antioxidant defense and inactivating enzymes involved in polysaccharide biosynthesis and metabolism. Disruption of bacterial signaling by DOPA modification reveals an infection containment strategy that weakens bacterial fitness and could be a blueprint for antivirulence approaches.