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

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.

Epigenetic and post-translational modifications in autophagy: biological functions and therapeutic targets

“…Similarly, G9a is capable of H3K9me/me2 on the promoter of Beclin1 and P62 to transcriptionally inhibit autophagy flux, and then induces vascular smooth muscle cells death, indicating that G9a may be a potent therapeutic target for cardiovascular diseases including aortic dissection. 56 In addition, Mtb phosphoribosyltransferase (MtbPRT) induces EHMT2-dependent H3K9me2/3 and reduces H3K9ac and H3K27ac by upregulating HDAC3 at the ATG5 and ATG7 promoter, which inhibit autophagy to promote Mtb survival 57 (Fig. 2a ).…”

“…On the one hand, EZH2 inhibition-triggered autophagy induces cell death of cancer cells 62 , 63 and aortic vascular smooth muscle cells, 64 liver injury 65 and also helps bacterial elimination. 57 In cancer cells, metastasis-associated 1 family member 2 (MTA2) first recognizes unmodified H3 with its SANT domain, then recruits EZH2 to a set of mTOR pathway-related genes, such as TSC2, RHOA, and DEPTOR, which are negative regulators of the mTOR signaling pathway, resulting in increased H3K27me3 accompanied by reduced H3K27ac at the promoters. As a result, the expression of mTOR pathway inhibitory genes is suppressed, which elicits mTOR activity and leads to autophagy inhibition.…”

Mycobacterium tuberculosis-macrophage interaction: Molecular updates

“…PknG either dually-regulates autophagy, promotes autophagy induction by competitively binding to AKT's pleckstrin homology (PH) domain, or inhibits autophagosome maturation to restrict autophagy flux by targeting the host small GTPase RAB14 (Ge et al, 2022). Other unknown escaping strategies include induction of histone hypermethylation in ATGs (Sengupta et al, 2021), direct autophagy inhibition by RELL1 (Feng et al, 2020), miRNA inhibition of autophagy by targeting critical AGTs (ULK1, ATG7, ATG16L1, ATG4c, and NPC1) located on the lysosomal membrane during Mtb infection Qu et al, 2021;Dong et al, 2022), and the implication of Mtb's sulfoglycolipids (SLs) and DIMs (Bah et al, 2020). While induction of host cell autophagy by starvation (starvation-induced autophagic elimination) is reported to kill the Mtb reference strain H37Rv via enhanced lysosomal delivery to mycobacterial phagosomes, its isolate Mtb Beijing strain, instead, easily resists and subdues this host blockade by exceptional upregulation of both Kxd1 and Plekhm2 genes' expression (Laopanupong et al, 2021).…”

Epigenetics in Tuberculosis: Immunomodulation of Host Immune Response

“…Several HDACs, such as HDAC1, HDAC2, HDAC3 and sirtuins, catalyze histone deacetylation out of which HDAC3 predominantly causes deacetylation during Mtb infection [ 61 ]. The suppression of IL12B expression by Mtb via HDAC1 is also shown [ 62 ].…”