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 mycobacterium tuberculosis (m. tuberculosis) is an important virulence factor,inactivation of which leads to reduced virulence of m. tuberculosis. esat-6 alone,or in complex with its chaperone cfp-10 (esat-6:cfp-10),is known to modulate host immune responses; however,the detailed mechanisms are not well understood. the structure of esat-6 or esat-6:cfp-10 complex does not suggest presence of enzymatic or dna-binding activities. therefore,we hypothesized that the crucial role played by esat-6 in the virulence of mycobacteria could be due to its interaction with some host cellular factors. using a yeast two-hybrid screening,we identified that esat-6 interacts with the host protein beta-2-microglobulin (β2m),which was further confirmed by other assays,like gst pull down,co-immunoprecipitation 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 β2m. we found that esat-6/esat-6:cfp-10 can enter into the endoplasmic reticulum where it sequesters β2m to inhibit cell surface expression of mhc-i-β2m complexes,resulting in downregulation of class i-mediated antigen presentation. interestingly,the esat-6:β2m complex could be detected in pleural biopsies of individuals suffering from pleural tuberculosis. our data highlight a novel mechanism by which m. tuberculosis may undermine the host adaptive immune responses to establish a successful infection. identification of such novel interactions may help us in designing small molecule inhibitors as well as effective vaccine design against tuberculosis. © 2014 sreejit et al.