Histone methyltransferase SUV 39H1 participates in host defense by methylating mycobacterial histone‐like protein HupB

Abstract

Host cell defense against an invading pathogen depends upon various multifactorial mechanisms, several of which remain undiscovered. Here, we report a novel defense mechanism against mycobacterial infection that utilizes the histone methyltransferase, SUV39H1. Normally, a part of the host chromatin, SUV39H1, was also found to be associated with the mycobacterial bacilli during infection. Its binding to bacilli was accompanied by trimethylation of the mycobacterial histone-like protein, HupB, which in turn reduced the cell adhesion capability of the bacilli. Importantly, SUV39H1-mediated methylation of HupB reduced the mycobacterial survival inside the host cell. This was also true in mice infection experiments. In addition, the ability of mycobacteria to form biofilms, a survival strategy of the bacteria dependent upon cell-cell adhesion, was dramatically reduced in the presence of SUV39H1. Thus, this novel defense mechanism against mycobacteria represents a surrogate function of the epigenetic modulator, SUV39H1, and operates by interfering with their cell-cell adhesion ability.

Involvement of Transcription Elongation Factor GreA in Mycobacterium Viability, Antibiotic Susceptibility, and Intracellular Fitness

“…The use of a nonpathogenic species, M. smegmatis, may have been a limitation of the present study. Although there is some evidence that M. smegmatis has been used as a model to study the function of interesting gene of M. tuberculosis (Wang et al, 2015(Wang et al, , 2017Yaseen et al, 2015Yaseen et al, , 2018, M. smegmatis isn't closely related to M. tuberculosis in genetically. Very recently, based on the comprehensive phylogenomic analyses and comparative genomic studies, M. smegmatis categorized as a novel classification of Mycobacterium is distinguished as a different genus comparing to M. tuberculosis.…”

Moonlighting activity of the epigenetic machinery restrains infection

“…In agreement with this finding, infection of mice with recombinant M. smegmatis yielded a higher amount of bacteria in lungs, liver, and spleen when the bacteria expressed HupB‐K138A, compared to bacteria expressing wild‐type HupB. Finally, Yaseen et al () report that treatment of Mtb with SUV39H1 markedly reduces biofilm formation in vitro and mycobacterial aggregation within phagosomes, demonstrating that trimethylation of HupB present in the Mtb envelope alters bacterial adherence.…”

“…Recently, several nucleomodulins or putative nucleomodulins were identified in Mtb (Sharma et al , ; Yaseen et al , ; Jose et al , ; Bhat et al , ; Wang et al , ). In this issue of The EMBO Journal , Yaseen et al () report the unsuspected finding that, conversely, host macrophages can use epigenetic modulators to modify bacterial proteins and reduce Mtb intracellular survival.…”

“…In order to investigate the epigenetic response of host macrophages to mycobacterial infection, Yaseen et al () analyzed the expression of several histone methyltransferases and demethylases in human macrophages infected with various Mycobacteria species. They observed that the histone H3K9 methyltransferase SUV39H1 was more abundant after infection of macrophages with mycobacteria, but not with other microorganisms, namely Escherichia coli and Candida glabrata .…”

Substrate recognition by the Pseudomonas aeruginosa EF-Tu methyltransferase EftM

“…Establishment of infection can also be both negatively and positively regulated by methylation of bacterial surface proteins by host-or pathogen-derived methyltransferases. The human protein SUV39H1, for example, methylates the crucial surface-exposed mycobacterial protein HupB which reduces bacterial adhesion and survival inside the host cell (6). In rickettsia, methylation of outer membrane protein B (OmpB) directly controls virulence (7): virulent species display lysine trimethylation of OmpB, which mediates host adhesion, attachment, and invasion, whereas avirulent strains possess monomethylated OmpB.…”