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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 Eis protein initiates suppression of host immune responses by acetylation of DUSP16/MKP-7
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Mycobacterium tuberculosis Eis protein initiates suppression of host immune responses by acetylation of DUSP16/MKP-7

机译：结核分枝杆菌Eis蛋白通过DUSP16 / MKP-7的乙酰化作用开始抑制宿主的免疫反应

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摘要

The intracellular pathogen Mycobacterium tuberculosis (Mtb) causes tuberculosis. Enhanced intracellular survival (Eis) protein, secreted by Mtb, enhances survival of Mycobacterium smegmatis (Msm) in macrophages. Mtb Eis was shown to suppress host immune defenses by negatively modulating autophagy, inflammation, and cell death through JNK-dependent inhibition of reactive oxygen species (ROS) generation. Mtb Eis was recently demonstrated to contribute to drug resistance by acetylating multiple amines of aminoglycosides. However, the mechanism of enhanced intracellular survival by Mtb Eis remains unanswered. Therefore, we have characterized both Mtb and Msm Eis proteins biochemically and structurally. We have discovered that Mtb Eis is an efficient Af-acetyltransferase, rapidly acetylating Lys55 of dual-specificity protein phosphatase 16 (DUSP16)/mitogen-activated protein kinase phosphatase-7 (MKP-7), a JNK-specific phosphatase. In contrast, Msm Eis is more efficient as an W'-acetyltransferase. We also show that Msm Eis acetylates aminoglycosides as readily as Mtb Eis. Furthermore, Mtb Eis, but not Msm Eis, inhibits LPS-induced .INK phosphorylation. This functional difference against DUSP16/MKP-7 can be understood by comparing the structures of two Eis proteins. The active site of Mtb Eis with a narrow channel seems more suitable for sequence-specific recognition of the protein substrate than the pocket-shaped active site of Msm Eis. We propose that Mtb Eis initiates the inhibition of JNK-dependent autophagy, phagosome maturation, and ROS generation by acetylating DUSP16/MKP-7. Our work thus provides insight into the mechanism of suppressing host immune responses and enhancing mycobacterial survival within macrophages by Mtb Eis.
机译：细胞内病原体结核分枝杆菌（Mtb）导致结核病。由Mtb分泌的增强的细胞内存活（Eis）蛋白可增强巨噬细胞中耻垢分枝杆菌（Msm）的存活。 Mtb Eis被证明可以通过JNK依赖性抑制活性氧（ROS）生成来负调节自噬，炎症和细胞死亡，从而抑制宿主的免疫防御。最近证明，Mtb Eis通过乙酰化氨基糖苷的多种胺来促进耐药性。然而，由Mtb Eis增强细胞内存活的机制仍未得到解答。因此，我们已经在生化和结构上表征了Mtb和Msm Eis蛋白。我们已经发现，Mtb Eis是一种有效的Af-乙酰基转移酶，可快速乙酰化双重特异性蛋白磷酸酶16（DUSP16）/有丝分裂原激活的蛋白激酶磷酸酶7（MKP-7）的Lys55，这是一种JNK特异性磷酸酶。相反，Eis女士作为W'-乙酰基转移酶更为有效。我们还显示Msm Eis和Mtb Eis一样容易乙酰化氨基糖苷。此外，Mtb Eis，而不是Msm Eis，抑制LPS诱导的.INK磷酸化。通过比较两种Eis蛋白的结构，可以了解针对DUSP16 / MKP-7的功能差异。与Msm Eis的袋状活性位点相比，具有窄通道的Mtb Eis活性位点似乎更适合于蛋白质底物的序列特异性识别。我们建议Mtb Eis通过乙酰化DUSP16 / MKP-7来启动对JNK依赖性自噬，吞噬体成熟和ROS生成的抑制作用。因此，我们的工作为Mtb Eis抑制宿主免疫应答和增强巨噬细胞内分枝杆菌存活的机制提供了见识。

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  • 作者

    Kyoung Hoon Kim; Doo Ri An; Jinsu Song; Ji Young Yoon; Hyoun Sook Kim; Hye Jin Yoon; Ha Na lm; Jieun Kim; Do Jin Kim; Sang Jae Lee; Ki-Hye Kim; Hye-Mi Lee; Hie-Joon Kim; Eun-Kyeong Jo; Jae Young Lee; Se Won Suh;

  • 作者单位

    Departments of Chemistry and College of Natural Sciences, Seoul National University, Seoul 151-742, Korea;

    Departments of Biophysics and Chemical Biology, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea;

    Departments of Chemistry and College of Natural Sciences, Seoul National University, Seoul 151-742, Korea;

    Departments of Chemistry and College of Natural Sciences, Seoul National University, Seoul 151-742, Korea;

    Departments of Chemistry and College of Natural Sciences, Seoul National University, Seoul 151-742, Korea;

    Departments of Chemistry and College of Natural Sciences, Seoul National University, Seoul 151-742, Korea;

    Departments of Biophysics and Chemical Biology, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea;

    Departments of Biophysics and Chemical Biology, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea;

    Departments of Chemistry and College of Natural Sciences, Seoul National University, Seoul 151-742, Korea;

    Departments of Chemistry and College of Natural Sciences, Seoul National University, Seoul 151-742, Korea;

    Departmentof Microbiology, Chungnam National University School of Medicine, Daejeon 301-747, Korea;

    Departmentof Microbiology, Chungnam National University School of Medicine, Daejeon 301-747, Korea;

    Departments of Chemistry and College of Natural Sciences, Seoul National University, Seoul 151-742, Korea;

    Departmentof Microbiology, Chungnam National University School of Medicine, Daejeon 301-747, Korea;

    Department of Life Science, Dongguk University-Seoul,Seoul 100-712, Korea;

    Departments of Chemistry and College of Natural Sciences, Seoul National University, Seoul 151-742, Korea, Departments of Biophysics and Chemical Biology, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea;

  • 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);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    Rv2416c; lysine acetylation; antituberculosis drug;

    机译：Rv2416c;赖氨酸乙酰化;抗结核药;

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