The sigma factors of Mycobacterium tuberculosis: regulation of the regulators
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One of the important determinants of virulence of Mycobacterium tuberculosis is adaptation to adverse conditions encountered in the host cells. The ability of Mycobacterium to successfully adapt to stress conditions is brought about by the expression of specific regulons effected by a repertoire of sigma factors. The induction and availability of sigma factors in response to specific stimuli is governed by a complex regulatory network comprising a number of proteins, including sigma factors themselves. A serine-threonine protein kinase-mediated signaling pathway adds another dimension to the mycobacterial sigma factor regulatory network. This review highlights the recent advances in understanding mycobacterial sigma factors, their regulation and contribution to bacterial pathogenesis.Keywords:
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When Bacillus subtilis is subjected to phosphate starvation, the Pho and sigma(B)-dependent general stress regulons are activated to elicit, respectively, specific and non-specific responses to this nutrient-limitation stress. A set of isogenic mutants, with a beta-galactosidase reporter gene transcriptionally fused to the inactivated target gene, was used to identify genes of unknown function that are induced or repressed under phosphate limitation. Nine phosphate-starvation-induced (psi) genes were identified: yhaX, yhbH, ykoL and yttP were regulated by the PhoP-PhoR two-component system responsible for controlling the expression of genes in the Pho regulon, while ywmG (renamed csbD), yheK, ykzA, ysnF and yvgO were dependent on the alternative sigma factor sigma(B), which controls the expression of the general stress genes. Genes yhaX and yhbH are unique members of the Pho regulon, since they are phosphate-starvation induced via PhoP-PhoR from a sporulation-specific sigma(E) promoter or a promoter that requires the product of a sigma(E)-dependent gene. Null mutations in key regulatory genes phoR and sigB showed that the Pho and sigma(B)-dependent general stress regulons of Bacillus subtilis interact to modulate the levels at which each are activated.
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The alternative sigma factor sigma(B) of Bacillus subtilis is responsible for the induction of the large general stress regulon comprising approximately 150-200 genes. YqgZ, a member of the sigma(B) regulon, resembles the global regulator Spx of the diamide stress regulon in B. subtilis. In this work we conducted a comprehensive transcriptome and proteome analysis of the B. subtilis wild-type 168 and its isogenic DeltasigB and DeltayqgZ mutants following exposure to 4% (v/v) ethanol stress, which led to the characterization of a 'subregulon' within the general stress response that is regulated by YqgZ. Activation and induction of sigma(B) are necessary but not sufficient for a full expression of all general stress genes. Expression of 53 genes was found to be positively regulated and the expression of 18 genes was negatively affected by YqgZ. The identification of the negatively regulated group represents a so far uncharacterized regulatory phenomenon observed in the DeltasigB mutant background that can now be attributed to the function of YqgZ. Due to the strict sigma(B)-dependent expression of YqgZ it was renamed to MgsR (modulator of the general stress response).
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Summary The Bacillus subtilis extracytoplasmic function (ECF) σ M factor is activated by cell envelope stress elicited by antibiotics, and by acid, heat, ethanol and superoxide stresses. Here, we have used several complementary approaches to identify genes controlled by σ M . In many cases, expression is only partially dependent on σ M because of both overlapping promoter recognition with other ECF σ factors and the presence of additional promoter elements. Genes regulated by σ M have a characteristic pattern of induction in response to cell envelope‐acting antibiotics as evidenced by hierarchical clustering analysis. σ M also contributes to the expression of the Spx transcription factor and thereby indirectly regulates genes of the Spx regulon. Cell envelope stress responses also include regulons controlled by σ W , σ B and several two‐component regulatory systems (e.g. LiaRS, YycFG, BceRS). Activation of the σ M regulon increases expression of proteins functioning in transcriptional control, cell wall synthesis and shape determination, cell division, DNA damage monitoring, recombinational repair and detoxification.
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ABSTRACT As with most life on Earth, the transition metal copper (Cu) is essential for the viability of the human pathogen Mycobacterium tuberculosis . However, infected hosts can also use Cu to control microbial growth. Several Cu-responsive pathways are present in M. tuberculosis , including the regulated in copper repressor (RicR) regulon, which is unique to pathogenic mycobacteria. In this work, we describe the contribution of each RicR-regulated gene to Cu resistance in vitro and to virulence in animals. We found that the deletion or disruption of individual RicR-regulated genes had no impact on virulence in mice, although several mutants had Cu hypersensitivity. In contrast, a mutant unable to activate the RicR regulon was not only highly susceptible to Cu but also attenuated in mice. Thus, these data suggest that several genes of the RicR regulon are required simultaneously to combat Cu toxicity in vivo or that this regulon is also important for resistance against Cu-independent mechanisms of host defense. IMPORTANCE Mycobacterium tuberculosis is the causative agent of tuberculosis, killing millions of people every year. Therefore, understanding the biology of M. tuberculosis is crucial for the development of new therapies to treat this devastating disease. Our studies reveal that although host-supplied Cu can suppress bacterial growth, M. tuberculosis has a unique pathway, the RicR regulon, to defend against Cu toxicity. These findings suggest that Cu homeostasis pathways in both the host and the pathogen could be exploited for the treatment of tuberculosis.
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In procaryotes such as Escherichia coli, transcriptional activation of heat shock genes in response to elevated temperature is caused primarily by transient increase in the amount of σ32 (rpoH gene product) specifically required for transcription from the heat shock promoters. The increase in σ32 level results from increased translation of rpoH mRNA and from stabilization of σ32 which is ordinarily very unstable. Some of the factors and cis-acting elements that constitute the complex regulatory circuits have been identified and characterized, but detailed mechanisms as well as nature of sensors and signals remain to be elucidated. Whereas this "classical"heat shock regulon (σ32 regulon) provides major protective functions against thermal stress, a second heat shock regulon mediated by σ32 (σ24) encodes functions apparently required under more extreme conditions, and is activated by responding to extracyto- plasmic signals. These regulons mediated by minor σ factors (σ32 in particular) appear to be conserved in most gram-negative bacteria, but not in gram-positive bacteria.
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ABSTRACT A consensus-directed search for ς B promoters was used to locate potential candidates for new ς B -dependent genes in Bacillus subtilis . Screening of those candidates by oligonucleotide hybridizations with total RNA from exponentially growing or ethanol-stressed cells of the wild type as well as a sigB mutant revealed 22 genes that required ς B for induction by ethanol. Although almost 50% of the proteins encoded by the newly discovered ς B -dependent stress genes seem to be membrane localized, biochemical functions have so far not been defined for any of the gene products. Allocation of the genes to the ς B -dependent stress regulon may indicate a potential function in the establishment of a multiple stress resistance. AldY and YhdF show similarities to NAD(P)-dependent dehydrogenases and YdbP to thioredoxins, supporting our suggestion that ς B -dependent proteins may be involved in the maintenance of the intracellular redox balance after stress.
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Alternative sigma factors allow bacteria to reprogram global transcription rapidly and to adapt to changes in the environment. Here we report on growth- and cell division-dependent sigma(32) regulon activity in Escherichia coli in batch culture. By analyzing sigma(32) expression in growing cells, an increase in sigma(32) protein levels is observed during the first round of cell division after exit from stationary phase. Increased sigma(32) protein levels result from transcriptional activation of the rpoH gene. After the first round of bulk cell division, rpoH transcript levels and sigma(32) protein levels decrease again. The late-logarithmic phase and the transition to stationary phase are accompanied by a second increase in sigma(32) levels and enhanced stability of sigma(32) protein but not by enhanced transcription of rpoH. Throughout growth, sigma(32) target genes show expression patterns consistent with oscillating sigma(32) protein levels. However, during the transition to early-stationary phase, despite high sigma(32) protein levels, the transcription of sigma(32) target genes is downregulated, suggesting functional inactivation of sigma(32). It is deduced from these data that there may be a link between sigma(32) regulon activity and cell division events. Further support for this hypothesis is provided by the observation that in cells in which FtsZ is depleted, sigma(32) regulon activation is suppressed.
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