Biology Department Seminar

Tuberculosis is a global health issue, because of increasing drug resistance and the difficulty in overcoming intracellular survival of Mycobacterium tuberculosis (Mtb). The highly successful human pathogen survives and multiplies within the macrophage cells. As intracellular survival of Mtb is critical in its pathogenesis, it is important to understand the survival strategies of this bacterium within macrophages. The Rv2416c gene of Mtb H37Rv strain was found to enhance intracellular survival of Mycobacterium smegmatis (Msm) in the human macrophage-like cell line U-937 and it was designated as eis (enhanced intracellular survival). The Mtb Eis protein was shown to suppress host immune defenses by negatively modulating autophagy, inflammation, and cell death through c-Jun N-terminal kinase (JNK)-dependent inhibition of reactive oxygen species (ROS) generation. Its N-acetyltransferase domain is essential for the regulation of ROS generation and proinflammatory responses. Nonpathogenic Msm contains a homologous eis gene (MSMEG_3513) that encodes a homolog of Mtb Eis (58% amino acid sequence identity). However, the fundamental question about the mechanism of enhanced mycobacterial survival by Mtb Eis has not yet been clarified. To better understand how Mtb Eis enhances mycobacterial survival in macrophages, we have carried out functional and structural characterization of Eis proteins from both Mtb and Msm. Our data show that Eis proteins from both Mtb and Msm are catalytically active as aminoglycoside N-acetyltransferases but only Mtb Eis is catalytically efficient as an N?-acetyltransferase that can acetylate Lys55 of the docking domain (or the kinase interaction motif) of DUSP16/MKP-7, a JNK-specific phosphatase in the host MAPK signaling pathways. And, crystal structure of Msm Eis in the paromomycin-bound form is revealing detailed interactions between an aminoglycoside antibiotic and Msm Eis. The crystal structure of Msm Eis in the paromomycin-bound form has been