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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Mycobacterium tuberculosis lipomannan blocks TNF biosynthesis by regulating macrophage MAPK-activated protein kinase 2 (MK2) and microRNA miR-125b
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Mycobacterium tuberculosis lipomannan blocks TNF biosynthesis by regulating macrophage MAPK-activated protein kinase 2 (MK2) and microRNA miR-125b

机译：结核分枝杆菌脂甘露聚糖通过调节巨噬细胞MAPK激活的蛋白激酶2（MK2）和microRNA miR-125b来阻断TNF的生物合成。

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摘要

Contact of Mycobacterium tuberculosis (M.tb) with the immune system requires interactions between microbial surface molecules and host pattern recognition receptors. Major M.tb-exposed cell envelope molecules, such as lipomannan (LM), contain subtle structural variations that affect the nature of the immune response. Here we show that LM from virulent M.tb (TB-LM), but not from avirulent Myocobacterium smegmatis (SmegLM), is a potent inhibitor of TNF biosynthesis in human macrophages. This difference in response is not because of variation in Toll-like receptor 2-dependent activation of the signaling kinase MAPK p38. Rather, TB-LM stimulation leads to destabilization of TNF mRNA transcripts and subsequent failure to produce TNF protein. In contrast SmegLM enhances MAPK-activated protein kinase 2 phosphorylation, which is critical for maintaining TNF mRNA stability in part by contributing microRNAs (miRNAs). In this context, human miRNA miR-125b binds to the 3' UTR region of TNF mRNA and destabilizes the transcript whereas miR-155 enhances TNF production by increasing TNF mRNA half-life and limiting expression of SHIP1, a negative regulator of the PI3K/ Akt pathway. We show that macrophages incubated with TB-LM and live M.tb induce high miR-125b expression and low miR-155 expression with correspondingly low TNF production. In contrast SmegLM and live M. smegmatis induce high miR-155 expression and low miR-125b expression with high TNF production. Thus, we identify a unique cellular mechanism underlying the ability of a major M.tb cell wall component, TB-LM, to block TNF biosynthesis in human macrophages, thereby allowing M.tb to subvert host immunity and potentially increase its virulence.
机译：结核分枝杆菌（M.tb）与免疫系统的接触需要微生物表面分子与宿主模式识别受体之间的相互作用。暴露于M.tb的主要细胞包膜分子（例如lipomannan（LM））包含影响免疫反应性质的细微结构变异。在这里，我们显示来自强毒结核分枝杆菌（TB-LM）而非无毒性耻垢分枝杆菌（SmegLM）的LM是人类巨噬细胞中TNF生物合成的有效抑制剂。这种响应差异不是由于信号激酶MAPK p38的Toll样受体2依赖性激活的变化。而是，TB-LM刺激导致TNF mRNA转录的不稳定，并随后产生TNF蛋白失败。相反，SmegLM增强了MAPK激活的蛋白激酶2磷酸化，这对于部分地通过贡献microRNA（miRNA）来维持TNF mRNA的稳定性至关重要。在这种情况下，人miRNA miR-125b与TNF mRNA的3'UTR区结合并破坏转录本的稳定性，而miR-155通过增加TNF mRNA的半衰期和限制SHIP1（PI3K /的负调控子）的表达来增强TNF的产生。 Akt途径。我们显示与TB-LM和活的M.tb孵育的巨噬细胞诱导高miR-125b表达和低miR-155表达，并相应降低TNF的产生。相反，SmegLM和活的耻垢分枝杆菌诱导高miR-155表达和低miR-125b表达，并产生高TNF。因此，我们确定了一种主要的M.tb细胞壁成分TB-LM阻止人类巨噬细胞中TNF生物合成的能力的独特细胞机制，从而使M.tb破坏了宿主的免疫力并潜在地增加了其毒性。

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    Murugesan V. S. Rajaram; Bin Ni; Jessica D. Morris; Michelle N. Brooks; Tracy K. Carlson; Baskar Bakthavachalu; Daniel R. Schoenberg; Jordi B. Torrelles; Larry S. Schlesinger;

  • 作者单位

    Center for Microbial Interface Biology;

    lntegrated Biomedical Science Graduate Program;

    Center for Microbial Interface Biology;

    Center for Microbial Interface Biology,Department of Microbiology;

    Center for Microbial Interface Biology,Department of Veterinary Biosciences;

    Center for RNA Biology and Department of Molecular and Cellular Biochemistry;

    Center for RNA Biology and Department of Molecular and Cellular Biochemistry;

    Center for Microbial Interface Biology,Department of Internal Medicine,Department of Microbial Infection and Immunity, Ohio State University, Columbus, OH 43210;

    Center for Microbial Interface Biology,Department of Microbiology,Department of Veterinary Biosciences,Department of Internal Medicine,Department of Microbial Infection and Immunity, Ohio State University, Columbus, OH 43210;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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