Mycobacterium tuberculosisRv3034c regulatesmTORC1andPPAR-γ dependant pexophagy mechanism to control redox levels in macrophages

Abstract

Mycobacterium tuberculosissurvives inside the macrophages by employing several host immune evasion strategies. Here, we reported a novel mechanism in whichM. tuberculosisacetyltransferase, encoded byRv3034c, induces peroxisome homeostasis to regulate host oxidative stress levels to facilitate intracellular mycobacterial infection. Presence ofM. tuberculosisRv3034c induces the expression of peroxisome biogenesis and proliferation factors such as Pex3, Pex5, Pex19, Pex11b, Fis-1 and DLP-1; while depletion ofRv3034cdecreased the expression of these molecules, thereby selective degradation of peroxisomes via pexophagy. Further studies revealed thatM. tuberculosisRv3034c inhibit induction of pexophagy mechanism by down-regulating the expression of pexophagy associated proteins (p-AMPK alpha, p-ULK-1, Atg5, Atg7, Beclin-1, LC3-II, TFEB and Keap-1) and adaptor molecules (NBR1 and p62). Inhibition was found to be dependent on the phosphorylation of mTORC1 and activation of peroxisome proliferator activated receptor-gamma. In order to maintain intracellular homeostasis during oxidative stress,M. tuberculosisRv3034c was found to induce degradation of dysfunctional and damaged peroxisomes through activation of Pex14 in infected macrophages. In conclusion, this is the first report which demonstrated thatM. tuberculosisacetyltransferase regulate peroxisome homeostasis in response to intracellular redox levels to favour mycobacterial infection in macrophage.