沈锡辉等《PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA》2021年

论文题目:T6SS translocates a micropeptide to suppress STING-mediated innate immunity by sequestering manganese

论文作者：Lingfang Zhu, Lei Xu, Chenguang Wang, Changfu Li, Mengyuan Li, Qinmeng Liu, Xiao Wang, Wenhui Yang, Damin Pan, Lingfei Hu, Yadong Yang, Zhiqiang Lu, Yao Wang, Dongsheng Zhou, Zhengfan Jiang, XihuiShen

细胞离子浓度是调解宿主先天免疫反应的关键因素，但目前尚未发现通过直接靶向金属离子来干扰宿主先天免疫反应的致病机制。我们揭示了一种假结核耶尔森氏菌（Yersinia pseudotuberculosis，Yptb）通过获取宿主细胞中的免疫刺激因子Mn2+来发挥毒力作用的新机制。研究发现假结核耶尔森氏菌能够通过VI 型分泌系统（T6SS）传递小蛋白TssS至宿主细胞中来增强其对宿主的致病性，而ΔtssS突变体菌株对宿主的致病性降低，同时发现ΔtssS诱导的宿主先天免疫反应显著增强，表明TssS抑制宿主抗细菌的天然免疫反应。进一步研究表明，TssS是一种Mn2+螯合蛋白，其Mn2+螯合能力对于抑制宿主抗细菌的先天免疫反应至关重要。此外，我们发现Mn2+通过激活干扰素基因刺激蛋白(STING) 介导的免疫反应来增强宿主抗细菌感染的宿主先天免疫反应，同时证实TssS通过鳌合宿主细胞中的Mn2+来抑制STING 介导的宿主的先天免疫反应，而TssS对STING的抑制作用影响宿主对感染细菌的清除。研究结果揭示了一种细菌通过调节宿主细胞内的金属离子可利用度来实现免疫逃逸的新策略，为T6SS致病机制的研究提供一个新的视角。

论文摘要：Cellular ionic concentrations are a central factor orchestrating hostinnate immunity, but no pathogenic mechanismthat perturbs hostinnate immunity by directly targeting metal ions has yet beendescribed. Here, we report a unique virulence strategy of Yersiniapseudotuberculosis (Yptb) involving modulation of the availabilityof Mn2+, an immunostimulatory metal ion in host cells. Weshowed that the Yptb type VI secretion system (T6SS) delivered amicropeptide, TssS, into host cells to enhance its virulence. Themutant strain lacking TssS (ΔtssS) showed substantially reducedvirulence but induced a significantly stronger host innate immuneresponse, indicating an antagonistic role of this effector in hostantimicrobial immunity. Subsequent studies revealed that TssS is aMn2+-chelating protein and that itsMn2+-chelating ability is essential for the disruption of host innate immunity. Moreover, weshowed that Mn2+ enhances the host innate immune response toYptb infection by activating the stimulator of interferon genes(STING)-mediated immune response. Furthermore, we demonstrated that TssS counteracted the cytoplasmic Mn2+ increase toinhibit the STING-mediated innate immune response by sequestering Mn2+. Finally, TssS-mediated STING inhibition sabotagedbacterial clearance in vivo. These results reveal a previously unrecognized bacterial immune evasion strategy involving modulationof the bioavailability of intracellular metal ions and provide a perspective on the role of the T6SS in pathogenesis.

论文链接：https://www.pnas.org/content/118/42/e2103526118