The Salmonella Secreted Effector SarA/SteE Mimics Cytokine Receptor Signaling to Activate STAT3
The Salmonella Secreted Effector SarA/SteE Mimics Cytokine Receptor Signaling to Activate STAT3
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DOI：
10.1016/j.chom.2019.11.012
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发表时间：
2020-01-08
影响因子：
30.3
通讯作者：
Ko, Dennis C.
中科院分区：
文献类型：
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作者：
Gibbs, Kyle D.;Washington, Erica J.;Ko, Dennis C.
细菌巧妙地利用和破坏宿主的信号传导。作为一个典型的例子，沙门氏菌使用两种3型分泌系统来注射促进沙门氏菌进入、建立细胞内生态位和调节免疫应答的效应蛋白。我们先前证明沙门氏菌抗炎反应激活剂SarA（Stm 2585、GogC、PagJ、SteE）激活宿主转录因子STAT 3以驱动免疫调节性STAT 3靶点的表达。在这里，我们演示的序列，功能和生化测量，SarA模拟糖蛋白130（gp 130，IL 6ST）的胞质结构域。SarA在YxxQ基序处被磷酸化，促进以比gp 130更大的亲和力与STAT 3结合。与经典的gp 130信号传导不同，SarA的功能是JAK独立的，但需要GSK-3，这是代谢和发育的关键调节因子。我们的研究结果表明，SarA经历宿主磷酸化招募STAT 3激活复合物，规避细胞因子受体激活。gp 130的效应物模拟表明GSK-3可以调节正常的细胞因子信号传导，可能使代谢和免疫串扰。
Bacteria masterfully co-opt and subvert host signal transduction. As a paradigmatic example, Salmonella uses two type-3 secretion systems to inject effector proteins that facilitate Salmonella entry, establishment of an intracellular niche, and modulation of immune responses. We previously demonstrated that the Salmonella anti-inflammatory response activator SarA (Stm2585, GogC, PagJ, SteE) activates the host transcription factor STAT3 to drive expression of immunomodulatory STAT3-targets. Here, we demonstrate-by sequence, function, and biochemical measurement-that SarA mimics the cytoplasmic domain of glycoprotein 130 (gp130, IL6ST). SarA is phosphorylated at a YxxQ motif, facilitating binding to STAT3 with greater affinity than gp130. Departing from canonical gp130 signaling, SarA function is JAK-independent but requires GSK-3, a key regulator of metabolism and development. Our results reveal that SarA undergoes host phosphorylation to recruit a STAT3-activating complex, circumventing cytokine receptor activation. Effector mimicry of gp130 suggests GSK-3 can regulate normal cytokine signaling, potentially enabling metabolic and immune crosstalk.