Downregulation of protein kinase C-α enhances intracellular survival of Mycobacteria: role of PknG

Background: Intracellular trafficking of mycobacteria is comprehensively dependent on the unusual regulation of host proteins. Recently, we have reported that infection of macrophages by Mycobacterium tuberculosis H37Rv (Rv) selectively downregulates the expression of PKC alpha while infection by Mycobacterium smegmatis (MS) does not. Results: Based on our earlier study, we have extrapolated for the first time that knockdown of PKCa, impairs phagocytosis of mycobacteria by macrophages while their intracellular survival is drastically increased. Mycobacterium bovis BCG (BCG) and Mycobacterium tuberculosis H37Ra (Ra) have also been shown to downregulate the expression of PKC alpha during the infection. Since PknG is uniquely expressed in BCG, Ra, Rv but not in MS and has been reported to promote intracellular survival of mycobacteria, led us to believe that PknG may be involved in such downregulation of PKC alpha. THP-1 cells infected with recombinant MS expressing PknG (MS-G), showed significant reduction in PKC alpha expression. In normal THP-1 cells survival of MS-G was enhanced as compared to MS, while their behavior in PKC alpha deficient cells could not be distinguished. The results strongly demonstrate that pathogenic mycobacteria recognize and then inhibit PKC alpha to circumvent phagocytosis and the hostile environment of macrophages. We emphasize that, this inhibition is controlled by PknG. Conclusions: All together, our data reveal a mechanism that shows substantial interdependence of PKC alpha with PknG, in sustaining mycobacterial infection.