Mycobacterium tuberculosis Phosphoribosyltransferase Promotes Bacterial Survival in Macrophages by Inducing Histone Hypermethylation in Autophagy-Related Genes.

Srabasti Sengupta,Avinash Sonawane,Snehasish Mishra,Barsa Nayak,Peter Sander,Michael Meuli

doi:10.3389/fcimb.2021.676456

Abstract

Mycobacterium tuberculosis (Mtb) inhibits autophagy to promote its survival in host cells. However, the molecular mechanisms by which Mtb inhibits autophagy are poorly understood. Here, we report a previously unknown mechanism in which Mtb phosphoribosyltransferase (MtbPRT) inhibits autophagy in an mTOR, negative regulator of autophagy, independent manner by inducing histone hypermethylation (H3K9me2/3) at the Atg5 and Atg7 promoters by activating p38-MAPK- and EHMT2 methyltransferase-dependent signaling pathways. Additionally, we find that MtbPRT induces EZH2 methyltransferase-dependent H3K27me3 hypermethylation and reduces histone acetylation modifications (H3K9ac and H3K27ac) by upregulating histone deacetylase 3 to inhibit autophagy. In summary, this is the first demonstration that Mtb inhibits autophagy by inducing histone hypermethylation in autophagy-related genes to promote intracellular bacterial survival.

Highlights

Pathogens are equipped with various strategies to dampen the host immune responses
An increase in H3K9ac could be attributed to reduced expression of HDAC3 due to inhibition of p38 expression (Figure 4G). These results suggest that Mycobacterium tuberculosis (Mtb) PRTmediated H3K9 hypermethylation followed by autophagy inhibition is facilitated by activation of the p38-The mitogen activated protein kinases (MAPK) signalling pathway
We found that the presence of Mtb phosphoribosyltransferase (Mtb PRT) in macrophages significantly down-regulated the expression of Microtubule-associated proteins 1A/1B light chain 3B (LC3)-II, ATG5 and ATG7

Summary

Introduction

Pathogens are equipped with various strategies to dampen the host immune responses. Upon infection, a battle between the host and the pathogen occurs, wherein the pathogen strives to command the host defence, and the host endeavours to eliminate the pathogen. Accumulating evidence demonstrates that pathogens can reprogram host gene expression to facilitate their survival by inducing various histone modifications such as methylation, acetylation, and phosphorylation that control the accessibility of activation or repression transcription factors to target genes (Hamon and Cossart, 2008; Allis and Jenuwein, 2016). Examples include Listeria monocytogens listeriolysin O which dephosphorylates H3 and deacetylates H4 to suppress host immunity factors (Hamon et al, 2007) and Mycobacterium tuberculosis (Mtb) ESAT-6 and LpqH proteins induce histone modifications into the MHC class II transactivator promoter to inhibit MHC-II expression and antigen presentation (Pennini et al, 2006; Kumar et al, 2012). There is considerable evidence that epigenetic modifications are critical determinants of bacterial virulence

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