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The Salmonella Secreted Effector SarA/SteE Mimics Cytokine Receptor Signaling to Activate STAT3.
Cell Host & Microbe ( IF 20.6 ) Pub Date : 2019-12-31 , DOI: 10.1016/j.chom.2019.11.012
Kyle D Gibbs 1 , Erica J Washington 2 , Sarah L Jaslow 1 , Jeffrey S Bourgeois 3 , Matthew W Foster 4 , Robyn Guo 1 , Richard G Brennan 2 , Dennis C Ko 5
Affiliation  

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.

中文翻译:

沙门氏菌分泌效应器 SarA/SteE 模拟细胞因子受体信号以激活 STAT3。

细菌巧妙地吸收和破坏宿主信号转导。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反应的效应蛋白。我们之前证明了沙门氏菌抗炎反应激活剂 SarA(Stm2585、GogC、PagJ、SteE)激活宿主转录因子 STAT3 以驱动免疫调节 STAT3 靶标的表达。在这里,我们通过序列、功能和生化测量证明 SarA 模拟了糖蛋白 130(gp130,IL6ST)的细胞质结构域。SarA 在 YxxQ 基序处被磷酸化,促进以比 gp130 更大的亲和力与 STAT3 结合。与典型的 gp130 信号不同,SarA 功能与 JAK 无关,但需要 GSK-3,代谢和发育的关键调节剂。我们的研究结果表明,SarA 经历宿主磷酸化以募集 STAT3 激活复合物,从而规避细胞因子受体激活。gp130 的效应子模拟表明 GSK-3 可以调节正常的细胞因子信号,从而可能实现代谢和免疫串扰。
更新日期:2019-12-31
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