title: Mycobacterium tuberculosis Eis protein initiates suppression of host immune responses by acetylation of DUSP16/MKP-7.
abstract: 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 N(ε)-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 N(α)-acetyltransferase. We also show that Msm Eis acetylates aminoglycosides as readily as Mtb Eis. Furthermore, Mtb Eis, but not Msm 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 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.
authors.affiliation: Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Kyoung Hoon
authors.initials: KH
authors.lastname: Kim
authors.forename: Doo Ri
authors.initials: DR
authors.lastname: An
authors.forename: Jinsu
authors.initials: J
authors.lastname: Song
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Yoon
authors.forename: Hyoun Sook
authors.initials: HS
authors.lastname: Kim
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Yoon
authors.forename: Ha Na
authors.initials: HN
authors.lastname: Im
authors.forename: Jieun
authors.initials: J
authors.lastname: Kim
authors.forename: Do Jin
authors.initials: DJ
authors.lastname: Kim
authors.forename: Sang Jae
authors.initials: SJ
authors.lastname: Lee
authors.forename: Ki-Hye
authors.initials: KH
authors.lastname: Kim
authors.forename: Hye-Mi
authors.initials: HM
authors.lastname: Lee
authors.forename: Hie-Joon
authors.initials: HJ
authors.lastname: Kim
authors.forename: Eun-Kyeong
authors.initials: EK
authors.lastname: Jo
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Se Won
authors.initials: SW
authors.lastname: Suh
mesh_terms: D000107:Acetylation; D000123:Acetyltransferases; D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism*; D001483:Base Sequence; D015153:Blotting, Western; D003001:Cloning, Molecular; D003460:Crystallization; D054637:Dual-Specificity Phosphatases / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli; D054884:Host-Pathogen Interactions / Q000276:immunology*; D006801:Humans; D007700:Kinetics; D008264:Macrophages; D051379:Mice; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020102:Mycobacterium smegmatis / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D017422:Sequence Analysis, DNA; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014961:X-Ray Diffraction
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D000123:Acetyltransferases; C430563:Eis protein, Mycobacterium tuberculosis; D054639:Mitogen-Activated Protein Kinase Phosphatases; C439065:DUSP16 protein, human; D054637:Dual-Specificity Phosphatases