T6SS translocates a micropeptide to suppress STING-mediated innate immunity by sequestering manganese
T6SS translocates a micropeptide to suppress STING-mediated innate immunity by sequestering manganese
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T6SS 易位微肽，通过隔离锰来抑制 STING 介导的先天免疫
DOI：
10.1073/pnas.2103526118
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Xihui Shen
中科院分区：
文献类型：
--
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;Xihui Shen
意义虽然新出现的证据表明，刺痛介导的免疫反应途径在微生物病原体感染中起着关键作用，但很少有细菌效应物针对这一途径的报道。在这里，我们发现了一种T6SS分泌的微肽TsSS，它在Yptb的发病机制中起着至关重要的作用。与以宿主蛋白或其他大分子为靶标的传统细菌效应器不同，TSSS通过螯合Mn2+来抑制STING寡聚和下游信号通路。因此，TSSs通过调节免疫刺激性Mn2+在宿主细胞中的可获得性，介导了一种先前未知的免疫逃避机制。这一发现揭示了一种通过微生物病原体调节刺痛途径的策略，为T6SS在发病机制中的作用提供了一个新的视角，并强调了微肽在病原体-宿主相互作用中的重要性。细胞离子浓度是调节宿主天然免疫的核心因素，但通过直接靶向金属离子扰乱宿主天然免疫的致病机制尚未被描述。在这里，我们报告了一种独特的假结核耶尔森菌(Yptb)毒力策略，涉及到调节宿主细胞中免疫刺激金属离子Mn2+的有效性。我们发现Yptb VI型分泌系统(T6SS)将一种微肽TsSS送入宿主细胞以增强其毒力。缺乏tsss的突变株(Δtsss)的毒力显著降低，但诱导了显著增强的宿主天然免疫反应，表明该效应分子在宿主抗菌免疫中具有拮抗作用。随后的研究表明，TsSS是一种与Mn2+离子螯合的蛋白，其对Mn2+的螯合能力是破坏宿主天然免疫所必需的。此外，我们还发现，Mn2+通过激活干扰素基因刺激物(STINT)介导的免疫反应来增强宿主对Yptb感染的先天免疫应答。此外，我们还证明了TSSS通过隔离Mn2+来抵消胞质中Mn2+的增加，从而抑制了STING介导的天然免疫反应。最后，TSSS介导的刺痛抑制破坏了细菌在体内的清除。这些结果揭示了一种以前未知的细菌免疫逃避策略，涉及到调节细胞内金属离子的生物有效性，并为T6SS在发病机制中的作用提供了一个前景。
Significance Although emerging evidence suggests that the STING-mediated immune response pathway plays a crucial role in microbial pathogen infection, few bacterial effectors have been reported to target this pathway. Here, we identified a T6SS-secreted micropeptide, TssS, which is crucial for the pathogenesis of Yptb. Distinct from traditional bacterial effectors that target host proteins or other macromolecules, TssS inhibits STING oligomerization and downstream signaling pathways by chelating Mn2+. Thus, TssS mediates a previously unrecognized immune evasion mechanism by modulating the availability of immunostimulatory Mn2+ in host cells. This finding reveals a strategy to modulate the STING pathway by microbial pathogens, provides a new perspective on the role of T6SS in pathogenesis, and highlights the importance of micropeptides in pathogen–host interactions. Cellular ionic concentrations are a central factor orchestrating host innate immunity, but no pathogenic mechanism that perturbs host innate immunity by directly targeting metal ions has yet been described. Here, we report a unique virulence strategy of Yersinia pseudotuberculosis (Yptb) involving modulation of the availability of Mn2+, an immunostimulatory metal ion in host cells. We showed that the Yptb type VI secretion system (T6SS) delivered a micropeptide, TssS, into host cells to enhance its virulence. The mutant strain lacking TssS (ΔtssS) showed substantially reduced virulence but induced a significantly stronger host innate immune response, indicating an antagonistic role of this effector in host antimicrobial immunity. Subsequent studies revealed that TssS is a Mn2+-chelating protein and that its Mn2+-chelating ability is essential for the disruption of host innate immunity. Moreover, we showed that Mn2+ enhances the host innate immune response to Yptb infection by activating the stimulator of interferon genes (STING)-mediated immune response. Furthermore, we demonstrated that TssS counteracted the cytoplasmic Mn2+ increase to inhibit the STING-mediated innate immune response by sequestering Mn2+. Finally, TssS-mediated STING inhibition sabotaged bacterial clearance in vivo. These results reveal a previously unrecognized bacterial immune evasion strategy involving modulation of the bioavailability of intracellular metal ions and provide a perspective on the role of the T6SS in pathogenesis.
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DOI：
10.1038/s41396-021-01093-8
发表时间：
2022-03
期刊：
The ISME journal
影响因子：
--
作者：
Li C;Zhu L;Wang D;Wei Z;Hao X;Wang Z;Li T;Zhang L;Lu Z;Long M;Wang Y;Wei G;Shen X
通讯作者：
Shen X
影响因子：
64.5
作者：
Ting SY;Bosch DE;Mangiameli SM;Radey MC;Huang S;Park YJ;Kelly KA;Filip SK;Goo YA;Eng JK;Allaire M;Veesler D;Wiggins PA;Peterson SB;Mougous JD
通讯作者：
Mougous JD
VI 型分泌系统运输 Zn2 以对抗多重应激和宿主免疫力
影响因子：
6.7
作者：
Wang T;Si M;Song Y;Zhu W;Gao F;Wang Y;Zhang L;Zhang W;Wei G;Luo ZQ;Shen X
通讯作者：
Shen X
由具有内在细胞进入特性的 T6SS 效应器介导的不依赖于接触的杀伤
影响因子：
16.6
作者：
Song L;Pan J;Yang Y;Zhang Z;Cui R;Jia S;Wang Z;Yang C;Xu L;Dong TG;Wang Y;Shen X
通讯作者：
Shen X
影响因子：
30.3
作者：
Meinzer, Ulrich;Barreau, Frederick;Hugot, Jean-Pierre
通讯作者：
Hugot, Jean-Pierre