Mycobacteria modulate host epigenetic machinery by Rv1988 methylation of a non-tail arginine of histone H3

Yaseen, Imtiyaz; Kaur, Prabhjot; Nandicoori, Vinay Kumar; Khosla, Sanjeev

doi:10.1038/ncomms9922

Cited by 136 publications

(113 citation statements)

References 48 publications

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“…These results may provide newer tools to explore the spliceosome components, assembly, cis-regulatory elements and their perturbation by external factors like virulent bacterial factors. Interestingly, in some recent reports involvement of mycobacterial factors in regulating host epigenetics has been reported [64, 65] and therefore provides sufficient indications that certain bacterial factors may also directly or indirectly influence the splicing and polyadenylation machinery. An interesting point to note here is that out of five different kinds of AS events, RI events are unique as retained introns can greatly influence the folding of nascent polypeptides.…”

Section: Discussionmentioning

confidence: 99%

Alternate splicing of transcripts shape macrophage response to Mycobacterium tuberculosis infection

2017

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Transcriptional reprogramming of macrophages upon Mycobacterium tuberculosis (Mtb) infection is widely studied; however, the significance of alternate splicing (AS) in shaping cellular responses to mycobacterial infections is not yet appreciated. Alternate splicing can influence transcript stability or structure, function and localization of corresponding proteins thereby altering protein stoichiometry and physiological consequences. Using comprehensive analysis of a time-series RNA-seq data obtained from human macrophages infected with virulent or avirulent strains of Mtb, we show extensive remodeling of alternate splicing in macrophage transcriptome. The global nature of this regulation was evident since genes belonging to functional classes like trafficking, immune response, autophagy, redox and metabolism showed marked departure in the pattern of splicing in the infected macrophages. The systemic perturbation of splicing machinery in the infected macrophages was apparent as genes involved at different stages of spliceosome assembly were also regulated at the splicing level. Curiously there was a considerable increase in the expression of truncated/non-translatable variants of several genes, specifically upon virulent infections. Increased expression of truncated transcripts correlated with a decline in the corresponding protein levels. We verified the physiological relevance for one such candidate gene RAB8B; whose truncated variant gets enriched in H37Rv infected cells. Upon tweaking relative abundance of longer or shorter variants of RAB8B transcripts by specialized transduction, mycobacterial targeting to lysosomes could be promoted or blocked respectively, which also resulted in corresponding changes in the bacterial survival. Our results show RAB8B recruitment to the mycobacterial phagosomes is required for phagosome maturation. Thus the abundance of truncated RAB8B variant helps virulent Mtb survival by limiting the RAB8B levels in the cells, a mechanism which we subsequently verified in human primary macrophages. Taken together we demonstrate alternate splicing as a new locus of intervention by Mtb and provide attractive alternative to exploit for novel drug targets against Mtb.

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Section: Discussionmentioning

confidence: 99%

Alternate splicing of transcripts shape macrophage response to Mycobacterium tuberculosis infection

2017

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“…Interestingly, a more recent study showed that Erm37, besides its role in protecting the mycobacterial ribosome from macrolides and lincosamides, is also involved in an epigenetic mechanism hijacking host macrophages’ gene expression control. In this study, Erm37 was shown to be secreted by M. tuberculosis and localized to the host nucleus where it interacts with chromatin and methylates histone H3 at H3R42, repressing the expression of genes involved in the first-line defense against pathogenic mycobacteria (Yaseen et al 2015). The antibiotic-induced expression of mycobacterial factors such as Erm37 or Eis (see “Drug inactivation” below), which are involved in both virulence and drug resistance, represents a dangerous evolution of infectious diseases against antibiotic chemotherapies.…”

Section: Specialized Resistance Mechanismsmentioning

confidence: 99%

Antibiotic resistance mechanisms in M. tuberculosis: an update

2016

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Treatment of tuberculosis (TB) has been a therapeutic challenge because of not only the naturally high resistance level of Mycobacterium tuberculosis to antibiotics but also the newly acquired mutations that confer further resistance. Currently standardized regimens require patients to daily ingest up to four drugs under direct observation of a healthcare worker for a period of 6–9 months. Although they are quite effective in treating drug susceptible TB, these lengthy treatments often lead to patient non-adherence, which catalyzes for the emergence of M. tuberculosis strains that are increasingly resistant to the few available anti-TB drugs. The rapid evolution of M. tuberculosis, from mono-drug-resistant to multiple drug-resistant, extensively drug-resistant and most recently totally drug-resistant strains, is threatening to make TB once again an untreatable disease if new therapeutic options do not soon become available. Here, I discuss the molecular mechanisms by which M. tuberculosis confers its profound resistance to antibiotics. This knowledge may help in developing novel strategies for weakening drug resistance, thus enhancing the potency of available antibiotics against both drug susceptible and resistant M. tuberculosis strains.

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“…Importantly, our finding that SUV39H1 acts to prevent mycobacterial infections, both in macrophages (THP1 as well as peritoneal) cells in culture and in mice infection studies, through its surrogate role as a methyltransferase of the mycobacterial protein HupB, adds a novel epigenetic paradigm to the duel between the host cell and the infecting pathogen. Our laboratory had previously shown that mycobacteria utilize a subset of its repertoire of secretory proteins to modulate the host cell by directly interacting with the epigenetic circuitry (Sharma et al , ; Yaseen et al , ). Here, we show that the host cells have also developed the ability to utilize components of its epigenetic circuitry to directly interact with the mycobacterial cells.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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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.

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Mycobacteria modulate host epigenetic machinery by Rv1988 methylation of a non-tail arginine of histone H3

Cited by 136 publications

References 48 publications

Alternate splicing of transcripts shape macrophage response to Mycobacterium tuberculosis infection

Alternate splicing of transcripts shape macrophage response to Mycobacterium tuberculosis infection

Antibiotic resistance mechanisms in M. tuberculosis: an update

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

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