<i>Mycobacterium tuberculosis</i> Eis protein initiates suppression of host immune responses by acetylation of DUSP16/MKP-7
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- Kyoung Hoon Kim
- Departments of aChemistry and
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- Doo Ri An
- Biophysics and Chemical Biology, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea;
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- Jinsu Song
- Departments of aChemistry and
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- Ji Young Yoon
- Departments of aChemistry and
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- Hyoun Sook Kim
- Departments of aChemistry and
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- Hye Jin Yoon
- Departments of aChemistry and
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- Ha Na Im
- Biophysics and Chemical Biology, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea;
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- Jieun Kim
- Biophysics and Chemical Biology, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea;
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- Do Jin Kim
- Departments of aChemistry and
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- Sang Jae Lee
- Departments of aChemistry and
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- Ki-Hye Kim
- Department of Microbiology, Chungnam National University School of Medicine, Daejeon 301-747, Korea; and
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- Hye-Mi Lee
- Department of Microbiology, Chungnam National University School of Medicine, Daejeon 301-747, Korea; and
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- Hie-Joon Kim
- Departments of aChemistry and
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- Eun-Kyeong Jo
- Department of Microbiology, Chungnam National University School of Medicine, Daejeon 301-747, Korea; and
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- Jae Young Lee
- Department of Life Science, Dongguk University-Seoul, Seoul 100-712, Korea
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- Se Won Suh
- Departments of aChemistry and
説明
<jats:p> The intracellular pathogen <jats:italic>Mycobacterium tuberculosis</jats:italic> ( <jats:italic>Mtb</jats:italic> ) causes tuberculosis. Enhanced intracellular survival (Eis) protein, secreted by <jats:italic>Mtb</jats:italic> , enhances survival of <jats:italic>Mycobacterium smegmatis</jats:italic> ( <jats:italic>Msm</jats:italic> ) in macrophages. <jats:italic>Mtb</jats:italic> 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. <jats:italic>Mtb</jats:italic> Eis was recently demonstrated to contribute to drug resistance by acetylating multiple amines of aminoglycosides. However, the mechanism of enhanced intracellular survival by <jats:italic>Mtb</jats:italic> Eis remains unanswered. Therefore, we have characterized both <jats:italic>Mtb</jats:italic> and <jats:italic>Msm</jats:italic> Eis proteins biochemically and structurally. We have discovered that <jats:italic>Mtb</jats:italic> Eis is an efficient <jats:italic>N</jats:italic> <jats:sup>ɛ</jats:sup> -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, <jats:italic>Msm</jats:italic> Eis is more efficient as an <jats:italic>N</jats:italic> <jats:sup>α</jats:sup> -acetyltransferase. We also show that <jats:italic>Msm</jats:italic> Eis acetylates aminoglycosides as readily as <jats:italic>Mtb</jats:italic> Eis. Furthermore, <jats:italic>Mtb</jats:italic> Eis, but not <jats:italic>Msm</jats:italic> Eis, inhibits LPS-induced JNK phosphorylation. This functional difference against DUSP16/MKP-7 can be understood by comparing the structures of two Eis proteins. The active site of <jats:italic>Mtb</jats:italic> Eis with a narrow channel seems more suitable for sequence-specific recognition of the protein substrate than the pocket-shaped active site of <jats:italic>Msm</jats:italic> Eis. We propose that <jats:italic>Mtb</jats:italic> 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 <jats:italic>Mtb</jats:italic> Eis. </jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 109 (20), 7729-7734, 2012-04-30
Proceedings of the National Academy of Sciences