The ESAT-6 Protein of Mycobacterium tuberculosis Interacts with Beta-2-Microglobulin (β2M) Affecting Antigen Presentation Function of Macrophage

ESAT-6, an abundantly secreted protein of ycobacte tuberculosis tuberculosis) an important virLilence fac inactivation of which leads to redLiced virulence of M. tuberculosis. ESAT-6 alone, or in complex with its chaperone CFP-10 (ESAT-6:CFP-10), is known to modulate host immLlne responses; however, the detailed mechanisms are not well understood. The strLlctLlre of ESAT-6 or ESAT-6:CFP-10 complex does not suggest presence of enzymatic or DNA-binding es. Therefore we hypothesized that the crucial role played by he virulence of mycobacteria raction with some host cellular factors. Using a yeast two-hybrid screening, we identified that ESAT-6 interacts with protein b a-2-microglobulin (beta 2M) which was fLirther confirmed by other assays, like GST pull down, coLinoprecipitation and surface plasmon resonance. The C-terminal six amino acid residues (90-95) of ESAT-6 were found to be essential for this interaction. ESAT-6, in complex with CFP-10, also interacts with 12m. We found that ESAT-6/ESAT6:CFP 10 can enter into the endoplasmic reticulum where it sequesters beta 2M to inhibit cell expression complexes, resulting in downregulation of class I-mediated antigen presentation. Interestingly, the ESAT-6:02M complex could be detected in pleural biopsies of individLials sLiffering from pleural tLlbercLllosis. Our data highlight a novel echanism by which tuberculosis may undermine the host adaptive immune responses to establish a successful nfection. Identification of sLich novel interactions may help us in designing small molecule inhibitors as well as effective vaccine design against tuberculosis.