Lsr2 is a nucleoid-associated protein that targets AT-rich sequences and virulence genes in<i>Mycobacterium tuberculosis</i>

Gordon, B. A.; Li, Yifei; Wang, Linru; Sintsova, Anna; Bakel, Harm van; Tian, Songhai; Navarre, William Wiley; Xia, Bin; Liu, Jun

doi:10.1073/pnas.0913551107

Cited by 203 publications

(273 citation statements)

References 56 publications

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“…Consistent with this, six different DNA binding regulators, namely cyclic AMP receptor protein (CRP) 6 (28), response regulator PhoP of the phoP-phoR two-component system (23,27), EspR protein (ESX-1 secreted protein regulator) (29), nucleoid-associated protein Lsr2 (30), response regulator MprA (31), and WhiB6 (32), are known to influence espACD expression. Two recent reviews implicate PhoP and EspR in regulating the espACD operon highlighting the importance of the PhoP-EspR-espACD regulatory circuit in the control of ESAT-6 secretion (33,34).…”

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confidence: 87%

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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confidence: 87%

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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“…The transcription termination factor Rho and nucleoid-associated proteins are two such factors that are implicated in the silencing of foreign genomic elements. Nucleoid-associated proteins selectively bind to xenogeneic DNA with AT contents higher than that of the genome and silence them (45,46). The Rho protein of E. coli was recently implicated in causing the premature transcription termination of horizontally acquired genes and prophages in the genome (47).…”

Section: Non-r-m Defense Systemsmentioning

confidence: 99%

Diverse Functions of Restriction-Modification Systems in Addition to Cellular Defense

Vasu

Nagaraja

2013

Microbiol Mol Biol Rev

521

462

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SUMMARY Restriction-modification (R-M) systems are ubiquitous and are often considered primitive immune systems in bacteria. Their diversity and prevalence across the prokaryotic kingdom are an indication of their success as a defense mechanism against invading genomes. However, their cellular defense function does not adequately explain the basis for their immaculate specificity in sequence recognition and nonuniform distribution, ranging from none to too many, in diverse species. The present review deals with new developments which provide insights into the roles of these enzymes in other aspects of cellular function. In this review, emphasis is placed on novel hypotheses and various findings that have not yet been dealt with in a critical review. Emerging studies indicate their role in various cellular processes other than host defense, virulence, and even controlling the rate of evolution of the organism. We also discuss how R-M systems could have successfully evolved and be involved in additional cellular portfolios, thereby increasing the relative fitness of their hosts in the population.

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“…We hypothesized that the effect of PhoP on espA may be mediated through Rv3676 and Lsr2, which are known to regulate espA (Gordon et al, 2010;Rickman et al, 2005). However, no obvious binding was detected to the Rv3676 or lsr2 promoters by either form of PhoP (data not shown), suggesting that neither Rv3676 nor Lsr2 mediates the regulatory effect of PhoP on espA.…”

Section: Phop and Regulation Of Espamentioning

confidence: 99%

“…Expression of espA was also altered in a mutant of the regulatory factor cAMP receptor protein (CRP), and a putative CRP binding site was identified upstream of espA (Rickman et al, 2005). Additionally, the nucleoid-associated protein Lsr2 binds to the ESX-1 genes esxA, esxB and espA (Gordon et al, 2010). However, its effect on ESX-1 activity is not yet known.…”

Section: Introductionmentioning

confidence: 99%

EspR, a regulator of the ESX-1 secretion system in Mycobacterium tuberculosis, is directly regulated by the two-component systems MprAB and PhoPR

et al. 2015

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EspR, a regulator of the ESX-1 secretion system in Mycobacterium tuberculosis, is directly regulated by the two-component systems MprAB and PhoPR INTRODUCTIONESX-1 (ESAT-6 secretion system-1) is a major virulence determinant of Mycobacterium tuberculosis, the causative agent of human tuberculosis. ESX-1 exports pathogenic and immunogenic proteins such as ESAT-6 (EsxA), EspA and other substrate proteins into host cells (Simeone et al., 2009). The secretion of EspA and ESAT-6 is mutually dependent, with deletion of espA resulting in loss of ESAT-6 secretion, and vice versa (Fortune et al., 2005). EspA is encoded within the espA operon, while esxA is located in RD-1 (Region of difference 1), which contains most ESX-1 genes (Mahairas et al., 1996). The intergenic region upstream of espA contains known or predicted binding sites for several different regulatory factors (Hunt et al., 2012;Pang et al., 2013;Rickman et al., 2005; Rosenberg et al., 2011), suggesting that ESX-1 activity could be modulated via altering espA expression.EspR, a key transcriptional regulator of ESX-1, directly regulates espA (Raghavan et al., 2008; Rosenberg et al., 2011). An espR mutant exhibited decreased transcription of the espA operon, loss of ESAT-6 secretion and reduced virulence (Raghavan et al., 2008). Higher-order oligomerization of EspR appears to be involved in cooperatively linking distant DNA sites, such as the three EspR binding sites in the espA promoter (Blasco et al., 2011; Rosenberg et al., 2011). Three EspR sites were also identified in the espR promoter (Blasco et al., 2012). However, these EspR sites are much closer than in the espA promoter, suggesting that EspR may have aAbbreviations: CRP, cAMP receptor protein; EMSA, electrophoresis mobility shift assay; ESX-1, ESAT-6 secretion system-1; L6, lineage 6; RD-1, Region of difference 1; TCS, two-component system.

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

Cited by 203 publications

References 56 publications

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

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

Diverse Functions of Restriction-Modification Systems in Addition to Cellular Defense

EspR, a regulator of the ESX-1 secretion system in Mycobacterium tuberculosis, is directly regulated by the two-component systems MprAB and PhoPR

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