The PPE2 protein of Mycobacterium tuberculosis translocates to host nucleus and inhibits nitric oxide production

Abstract

Mycobacterium tuberculosis, the bacterium that causes tuberculosis, is one of the most successful pathogens of humans. It has evolved several adaptive skills and evasion mechanisms to hijack the immunologically educated host to suit its intracellular lifestyle. Here, we show that one of the unique PPE family member proteins of M. tuberculosis, PPE2, can limit nitric oxide (NO) production by inhibiting inos gene transcription. PPE2 protein has a leucine zipper DNA-binding motif and a functional nuclear localization signal. PPE2 was translocated into the macrophage nucleus via the classical importin α/β pathway where it interacted with a GATA-binding site overlapping with the TATA box of inos promoter and inhibited NO production. PPE2 prolonged intracellular survival of a surrogate bacterium M. smegmatis in vitro as well as in vivo. This information are likely to improve our knowledge of host-pathogen interactions during M. tuberculosis infection which is crucial for designing effective anti-TB therapeutics.

Modulation of macrophage defense responses by Mycobacterial persistence protein MprA (Rv0981) in human THP-1 cells: effect of single amino acid variation on host-pathogen interactions

“…However, the SNV in MprA* does not map in this region. (Bhat et al, 2017). Rv3423.1, a mycobacterial histone acetyltransferase, is known to co-localize with chromatin in macrophage nucleus while it was secreted into the culture medium by the virulent strain of the bacteria (Jose et al, 2016).The authors demonstrated that Rv3423.1 protein localizes with the chromatin and brings about histone acetylation.…”

Molecular Basis Underlying Host Immunity Subversion by Mycobacterium tuberculosis PE/PPE Family Molecules

“…PPE2 imitates a eukaryotic transcription factor by the classical importin a/b pathway, binds to upstream regulatory sequences of inducible nitric oxide synthase (iNOS), and regulates iNOS transcription. PPE2 may aid the bacteria to suppress NO production (Bhat et al, 2017). Diverse roles of PE/PPE protein in the host immunity are summarized in Figure 2.…”

Nitric Oxide in the Pathogenesis and Treatment of Tuberculosis

“…The Proline-Proline-Glutamate (PPE) family of proteins are particularly abundant in pathogenic Mycobacterial species such as Mtb (Bhat et al, 2017 ). Recent evidence indicates that these proteins can act as repressive transcription factors in the nucleus of host macrophages to suppress NOS2 expression and thereby reduce the release of the anti-mycobacterial NO molecule (Bhat et al, 2017 ).…”

“…The Proline-Proline-Glutamate (PPE) family of proteins are particularly abundant in pathogenic Mycobacterial species such as Mtb (Bhat et al, 2017 ). Recent evidence indicates that these proteins can act as repressive transcription factors in the nucleus of host macrophages to suppress NOS2 expression and thereby reduce the release of the anti-mycobacterial NO molecule (Bhat et al, 2017 ). In addition, soon after Mtb infection, macrophages produce IL-10 which induces the phosphorylation and activation of the transcription factor signal transducer and activator of transcription (STAT3) (Queval et al, 2016 ).…”