Reactive Persulfides from Salmonella Typhimurium Downregulate Autophagy-Mediated Innate Immunity in Macrophages by Inhibiting Electrophilic Signaling
Reactive Persulfides from Salmonella Typhimurium Downregulate Autophagy-Mediated Innate Immunity in Macrophages by Inhibiting Electrophilic Signaling
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DOI：
10.1016/j.chembiol.2018.08.007
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发表时间：
2018-11-15
影响因子：
8.6
通讯作者：
Akaike, Takaaki
中科院分区：
文献类型：
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作者：
Khan, Shahzada;Fujii, Shigemoto;Akaike, Takaaki
半胱氨酸、过硫化物等活性过硫化物是由沙门氏菌等细菌在硫代谢过程中产生的。细菌活性硫化物在宿主-病原菌相互作用中的生物学意义仍值得研究。我们发现，鼠伤寒沙门氏菌LT2产生的活性过硫化物通过代谢8-硝基鸟苷3‘，5’-环单磷酸(8-Nitro-cGMP)来调节巨噬细胞的自噬。8-Nitro-cGMP是活性氧物种和一氧化氮信号的亲电产物。8-Nitro-cGMP信号是有效的自噬介导的清除沙门氏菌感染巨噬细胞所必需的。在被感染的细胞中，8-硝基-cGMP引起细菌表面蛋白cGMP加合物的形成(S鸟苷)，从而引发自噬相关蛋白P62和LC3-II募集到细胞内的细菌。我们还发现，沙门氏菌产生的反应性过硫化物通过减少细胞内8-硝基-cGMP的含量来下调这种自噬，从而抑制亲电信号。这些数据揭示了细菌衍生的反应性过硫化物通过抑制抗细菌自噬而起的致病作用。
Reactive persulfides such as cysteine persulfide and glutathione persulfide are produced by bacteria including Salmonella during sulfur metabolism. The biological significance of bacterial reactive persulfides in host-pathogen interactions still warrants investigation. We found that reactive persulfides produced by Salmonella Typhimurium LT2 regulate macrophage autophagy via metabolizing 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), an electrophilic product of reactive oxygen species and nitric oxide signaling. 8-Nitro-cGMP signaling was required for efficient autophagy-mediated clearance of Salmonella from infected macrophages. In the infected cells, 8-nitro-cGMP caused cGMP adduct formation (S-guanylation) of bacterial surface proteins, which triggered recruitment of autophagy-related proteins p62 and LC3-II to the intracellular bacteria. We also found that Salmonella-produced reactive persulfides downregulated this autophagy by decreasing cellular 8-nitro-cGMP content, thereby inhibiting electrophilic signaling. These data reveal a pathogenic role of bacteria-derived reactive persulfides via suppression of anti-bacterial autophagy.