Abstract
Crystal structure of the secretory chorismate mutase protein of Mycobacterium tuberculosis (MtbCM) reveals presence of a proline rich region on its surface that serve as a recognition site for protein-protein interaction. This study shows that MtbCM upregulates IL-10 which favors M. tuberculosis by affecting PKCε-MKP-1-p38 MAPK signaling. MtbCM translocates to the Golgi-network where it interacts with AKAP9 via its SH3-binding domain to inhibit AKAP9-PKCε interaction and reducing PKCε phosphorylation. In the absence of phosphorylated PKCε, IRAK3 fails to stabilize MKP-1 resulting in higher p38 MAPK activation and IL-10 production. M. smegmatis expressing MtbCM survived better in infected mice. Mutation in SH3-binding domain ablated MtbCM-AKAP9 interaction resulting in IL-10 production and decreased bacterial survival. This study highlights the importance of SH3-binding domain in host-pathogen interaction and a role of MtbCM in modulation of cytokine response and mycobacterial virulence in addition to its role in shikimate pathway.