The specialized secretory apparatus ESX‐1 is essential for DNA transfer in <i>Mycobacterium smegmatis</i>

Coros, Abbie M.; Callahan, Brian P.; Battaglioli, Eric J.; Derbyshire, Keith M.

doi:10.1111/j.1365-2958.2008.06299.x

Cited by 121 publications

(159 citation statements)

References 51 publications

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“…A second locus involved in ESX-1 secretion (Rv3614c-espA) (29) is also a target of Lsr2 (Dataset S1). The equivalent ESX-1 region in M. smegmatis (MSMEG_0055-MSMEG_0083) that is involved in DNA transfer (30,31) is also bound by Lsr2 (Datasets S2 and S3). Other well-established virulence factors include the cell-wall lipid phthiocerol dimycocerosates (PDIMs) (32,33) and their closely related phenolic glycolipids (PGLs) (34).…”

Section: Lsr2mentioning

confidence: 99%

Lsr2 is a nucleoid-associated protein that targets AT-rich sequences and virulence genes inMycobacterium tuberculosis

Gordon

Li²,

Wang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

191

250

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Bacterial nucleoid-associated proteins play important roles in chromosome organization and global gene regulation. We find that Lsr2 of Mycobacterium tuberculosis is a unique nucleoid-associated protein that binds AT-rich regions of the genome, including genomic islands acquired by horizontal gene transfer and regions encoding major virulence factors, such as the ESX secretion systems, the lipid virulence factors PDIM and PGL, and the PE/PPE families of antigenic proteins. Comparison of genome-wide binding data with expression data indicates that Lsr2 binding results in transcriptional repression. Domain-swapping experiments demonstrate that Lsr2 has an N-terminal dimerization domain and a C-terminal DNA-binding domain. Nuclear magnetic resonance analysis of the DNA-binding domain of Lsr2 and its interaction with DNA reveals a unique structure and a unique mechanism that enables Lsr2 to discriminately target AT-rich sequences through interactions with the minor groove of DNA. Taken together, we provide evidence that mycobacteria have employed a structurally distinct molecule with an apparently different DNA recognition mechanism to achieve a function similar to the Enterobacteriaceae H-NS, likely coordinating global gene regulation and virulence in this group of medically important bacteria.

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Section: Lsr2mentioning

confidence: 99%

Lsr2 is a nucleoid-associated protein that targets AT-rich sequences and virulence genes inMycobacterium tuberculosis

Gordon

Li²,

Wang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

191

250

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“…Apart from the reported plasmid-mediated conjugal transfer in Mycobacterium marinum (31), a chromosomal transfer mechanism similar to eukaryotic meiotic-like recombination was described for M. smegmatis (16). Whereas the first mechanism involves a mega-plasmid, encoding elements of type IV and type VII secretion systems, present in similar form also in Mycobacterium kansasii and Mycobacterium yongonense (32), chromosomal HGT in M. smegmatis requires a set of genes with donor and recipient functions, as well as genes conferring mating identity linked to an ESX-1 type VII system (12,16,33,34). Patterns of RC1 and RC2 are shown in Fig.…”

Section: Discussionmentioning

confidence: 99%

Key experimental evidence of chromosomal DNA transfer among selected tuberculosis-causing mycobacteria

Boritsch

Khanna

Pawlik

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Horizontal gene transfer (HGT) is a major driving force of bacterial diversification and evolution. For tuberculosis-causing mycobacteria, the impact of HGT in the emergence and distribution of dominant lineages remains a matter of debate. Here, by using fluorescenceassisted mating assays and whole genome sequencing, we present unique experimental evidence of chromosomal DNA transfer between tubercle bacilli of the early-branching Mycobacterium canettii clade. We found that the obtained recombinants had received multiple donor-derived DNA fragments in the size range of 100 bp to 118 kbp, fragments large enough to contain whole operons. Although the transfer frequency between M. canettii strains was low and no transfer could be observed among classical Mycobacterium tuberculosis complex (MTBC) strains, our study provides the proof of concept for genetic exchange in tubercle bacilli. This outstanding, now experimentally validated phenomenon presumably played a key role in the early evolution of the MTBC toward pathogenicity. Moreover, our findings also provide important information for the risk evaluation of potential transfer of drug resistance and fitness mutations among clinically relevant mycobacterial strains.recombination | DNA transfer | tuberculosis | Mycobacterium canettii | evolution

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“…In fact, ESX-1 was shown to regulate DNA conjugation of the nonpathogenic M. smegmatis (49,50). In contrast, the espACD operon is absent in M. smegmatis (43) and is perhaps indicative of its direct role in virulence mechanisms.…”

Section: Discussionmentioning

confidence: 99%

EspR-dependent ESAT-6 Protein Secretion of Mycobacterium tuberculosis Requires the Presence of Virulence Regulator PhoP

Kumar

Goyal

Bansal

et al. 2016

Journal of Biological Chemistry

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Attenuation of Mycobacterium bovis BCG strain is related to the loss of the RD1-encoded ESX-1 secretion system. The ESX-1 system secretes virulence factor ESAT-6 that plays a critical role in modulation of the host immune system, which is essential for establishment of a productive infection. Previous studies suggest that among the reasons for attenuation of Mycobacterium tuberculosis H37Ra is a mutation in the phoP gene that interferes with the ESX-1 secretion system and inhibits secretion of ESAT-6. Here, we identify a totally different and distinct regulatory mechanism involving PhoP and transcription regulator EspR on transcriptional control of the espACD operon, which is required for ESX-1-dependent ESAT-6 secretion. Although both of these regulators are capable of influencing espACD expression, we show that activation of espACD requires direct recruitment of both PhoP and EspR at the espACD promoter. The most fundamental insights are derived from the inhibition of EspR binding at the espACD regulatory region of the phoP mutant strain because of PhoP-EspR protein-protein interactions. Based on these results, a model is proposed suggesting how PhoP and EspR protein-protein interactions contribute to activation of espACD expression and, in turn, control ESAT-6 secretion, an essential pathogenic determinant of M. tuberculosis. Together, these results have significant implications on the mechanism of virulence regulation of M. tuberculosis.Mycobacterium tuberculosis uses the ESX-1 secretion system to transport virulence factors in host cells (1-5). ESX-1 secretion system is encoded by the genes of the esx-1 locus, which is highly conserved in members of the M. tuberculosis complex and in other pathogenic mycobacteria (5-9). The best known ESX-1 substrates, the secreted proteins EsxA (ESAT-6) and EsxB (CFP10), have been implicated in the majority of the ESX-1-dependent modulations of host cell defense (10 -19) and therefore are considered to be essential for virulence (12)(13)(14). Consistently, deletion of the esx-1 locus abrogates ESX-1-dependent secretion and strongly attenuates M. tuberculosis (15,20). Notably, the genes encoding esx-1, located within the M. tuberculosis RD1 locus, are absent in the attenuated Mycobacterium bovis BCG and the potential vaccine strain Mycobacterium microti (15,17). However, a chromosomally unlinked non-RD1 locus (Rv3616c-Rv3615c-Rv3614c, also designated as espA, espC, and espD) is essential for ESX-1 function (13, 21). In fact, EspA and EspC proteins themselves are substrates of the ESX-1 secretion system, thus constituting mutually dependent secretion of substrates, a notable feature of this secretion system. More recently, EspA of the tubercle bacilli has been implicated as a critical mediator of bacterial cell wall integrity and ESX-1-dependent virulence regulation (22).ESX-1 represents the first and the most characterized member of the ESX secretion family. Although intracellular concentrations of ESAT-6 are similar in both virulent M. tuberculosis H37Rv and the attenuated...

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The specialized secretory apparatus ESX‐1 is essential for DNA transfer in Mycobacterium smegmatis

Cited by 121 publications

References 51 publications

Lsr2 is a nucleoid-associated protein that targets AT-rich sequences and virulence genes inMycobacterium tuberculosis

Lsr2 is a nucleoid-associated protein that targets AT-rich sequences and virulence genes inMycobacterium tuberculosis

Key experimental evidence of chromosomal DNA transfer among selected tuberculosis-causing mycobacteria

EspR-dependent ESAT-6 Protein Secretion of Mycobacterium tuberculosis Requires the Presence of Virulence Regulator PhoP

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