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

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

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2021.676456

DOI=10.3389/fcimb.2021.676456

ISSN=2235-2988

ABSTRACT=<p><italic>Mycobacterium tuberculosis (Mtb)</italic> inhibits autophagy to promote its survival in host cells. However, the molecular mechanisms by which <italic>Mtb</italic> inhibits autophagy are poorly understood. Here, we report a previously unknown mechanism in which <italic>Mtb</italic> phosphoribosyltransferase (<italic>Mtb</italic>PRT) inhibits autophagy in an mTOR, negative regulator of autophagy, independent manner by inducing histone hypermethylation (H3K9me2/3) at the <italic>Atg5</italic> and <italic>Atg7</italic> promoters by activating p38-MAPK- and EHMT2 methyltransferase-dependent signaling pathways. Additionally, we find that <italic>Mtb</italic>PRT 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 <italic>Mtb</italic> inhibits autophagy by inducing histone hypermethylation in autophagy-related genes to promote intracellular bacterial survival.</p>