Department of Genetics, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Kerklaan 30, 9751 NN Haren, The Netherlands
Correspondence
Oscar P. Kuipers
o.p.kuipers{at}biol.rug.nl
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ABSTRACT |
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Overview |
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B. subtilis is a soil-dwelling organism. In order to cope with the strong nutritional and physical fluctuations related to such an environment, this bacterium developed a wide arsenal of survival strategies. These processes can be conveniently observed in the laboratory by growing B. subtilis under batch-fermentation conditions. At the end of the exponential growth phase, when nutrients become limiting for optimal growth, B. subtilis cells start to synthesize a complex motility and chemotaxis system, which, in a natural habitat, would enable them to search for nutrients in the environment. If nutritional limitation continues, these motile cells enter the stationary growth phase, and start to secrete degradative enzymes such as proteases to liberate nutrients from alternative resources that are normally difficult to access. In addition, cells start to produce antibiotics to fight off possible competitors. Prolonged nutritional stress results in the development of competence, and ultimately in sporulation of the bacterial population. Sporulation provides the bacterium with a way to survive extended harsh environmental conditions.
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Genetically competent B. subtilis cells |
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Priming of comK expression |
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Transcriptional repression of comK expression |
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AbrB is not the only regulator which inhibits transcription of the comK promoter. Expression of comK is sensitive to the amino acid composition of the medium. Amino-acid-mediated repression of several B. subtilis genes has been shown to depend on a GTP-binding transcription factor, CodY (Slack et al., 1995). CodY senses the intracellular GTP concentration as an indication of the nutritional conditions in the medium, and regulates many stationary growth phase genes such as the dipeptide transport operon dpp, but also for example spo0A (Ratnayake-Lecamwasam et al., 2001
). A codY mutation alleviated the amino-acid-imposed control of comK expression, and DNA-footprinting analyses revealed that CodY occupies the RNA polymerase binding site of the comK promoter as well (Serror & Sonenshein, 1996
).
In an extensive genetic analysis, Hoa et al. (2002) identified a third repressor of the comK promoter. Overexpression of the gene ykuW inhibited transcription of comK, and a knockout of ykuW resulted in ComK overproduction. ykuW was renamed rok, an acronym for repressor of comK. Rok binds and represses not only the comK promoter but also its own promoter. High levels of ComK repress rok expression as well, and it was shown that ComK binds specifically to the promoter of rok. The ComK-dependent inhibition of rok expression appears to transform the Rok control of comK transcription into a positive feedback loop. Presumably, Rok fulfils a more pleiotropic role in B. subtilis as changes in expression levels of this protein not only influence comK expression but also affect sporulation. By now a total of five different transcription factors have been identified which control the comK promoter, a rather remarkable number for a prokaryotic promoter.
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Cell-density-dependent induction of competence |
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The competence-stimulating factor (CSF) was the second competence pheromone identified. Amino acid sequence analysis indicated that this pheromone is a pentapeptide with an amino acid sequence similar to the C-terminal part of a 40 amino acid long secreted protein, PhrC (Solomon et al., 1996). How processing of PhrC to CSF occurs is unknown (for clarity we will use here the nomenclature PhrC instead of CSF). Also PhrC exerts its quorum-sensing activity at the level of srfA transcription, and requires ComP and ComA for its activity. However, the stimulatory effect of PhrC on srfA expression also requires the oligopeptide permease Spo0K, suggesting that sensing of this pheromone occurs intracellularly (Lazazzera et al., 1997
). Upstream of phrC, the gene rapC is located. Genetic studies indicated that RapC is a negative regulator of srfA expression and probably dephosphorylates ComA
P (Solomon et al., 1996
). On the basis of a homologous system involved in sporulation (RapA/PhrA), it is supposed that PhrC inhibits RapC activity (phr stands for phosphatase regulator). Thus when PhrC levels rise sufficiently, RapC activity is repressed, ComA
P levels accumulate, and srfA/comS expression increases (Solomon et al., 1996
). So both pheromones, ComX and PhrC, stimulate expression of srfA/comS. Why B. subtilis uses a double quorum-sensing pathway for this process is not clear.
The concentration-dependent effectiveness of antibiotics explains why surfactin production depends on the accumulation of congeners. Yet quorum sensing may also have an important function in the genetic transformation process. Due to a RecA-based homologous recombination system active during competence, the efficiency of recombination and integration with the B. subtilis genome largely depends upon the measure of DNA sequence homology. Consequently, competent B. subtilis cells are transformed most efficiently with DNA from congeners. It is as if competence has primarily evolved to exchange genetic material within the species. This is even more apparent for Haemophilus influenzae and Neisseria gonorrhoeae (Lorenz & Wackernagel, 1994). In these bacteria, DNA binding and DNA uptake depend on specific sequence motifs dispersed over the genome as a result of which only DNA from the same or closely related species can be taken up. For Streptococcus pneumoniae it was shown that the development of competence is accompanied by lysis and DNA release of a subfraction of the population, and both processes appeared to be stimulated by the same quorum-sensing regulation pathway (Steinmoen et al., 2002
). Therefore, natural competence can be considered as the bacterial attempt at a sexual life-cycle (Redfield, 1988
). As the preferred donor DNA presumably originates from dead and lysed congeners, the cell density dependence of competence development may therefore have become an evolutionarily valuable asset.
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Post-translational control |
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Expression of neither mecA nor clpC changes dramatically during the transition to the stationary growth phase. The question of how the MecA/ClpC-mediated inactivation of ComK is alleviated remained unanswered, until it was observed that purified ComS inhibited the in vitro formation of a stable ternary ComK/MecA/ClpC complex (Turgay et al., 1997). It was later shown that ComS binds to MecA and stimulates the degradation of both proteins by the ClpCP protease complex (Ogura et al., 1999
; Persuh et al., 1999
). In conclusion, synthesis of ComS protects ComK from degradation so that auto-stimulation of comK expression is initiated. Thus the competence pheromones ComX and PhrC, which stimulate comS transcription, ultimately control comK expression on the post-translational level, by means of regulated proteolysis of ComK.
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More research, more regulators |
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A regulator which does influence competence development is SinR. The sin locus encodes another regulatory couple of which the activity extends beyond a single adaptive process. The first protein encoded by this bicistronic operon, SinI, represses the activity of the transcriptional regulator SinR, encoded by the second gene (Gaur et al., 1988). A sinR disruption results in non-motile, filamentous cells, and a strong reduction in competence, whereas overproduction of SinR blocks sporulation and related protease production. The regulation of SinR is complex, and control at both the transcriptional and (post)translational level seems to occur (Smith, 1993
). Transition from exponential to stationary growth is accompanied by an increase in SinI production. SinI shows similarity with the C-terminal part of SinR, and inactivates SinR by forming a heteromultimer with this protein (Bai et al., 1993
). The position of SinR in the competence signal transduction cascade is somewhat controversial. Liu et al. (1996)
suggested that SinR is required for optimal production of ComS, whereas Hahn et al. (1996)
presented evidence suggesting that SinR is directly involved in comK transcription. Recently, more evidence for the latter proposition has been found. It appeared that SinR acts negatively on rok transcription, and that inactivation of rok could bypass the requirement of SinR for comK expression (Hoa et al., 2002
).
One of the latest additions to the list of known competence regulators is YlbF (Tortosa et al., 2000). A disruption in ylbF affects both competence and sporulation. Although the exact function of YlbF is unknown, genetic studies suggest that this protein is required for the production of sufficient amounts of ComS. Actually, the production of ComS is rather complex since it also requires polynucleotide phosphorylase (Pnp) (Luttinger et al., 1996
). Pnp is involved in RNA stability, and besides stimulating the synthesis of surfactin synthetase and ComS, this RNA-binding protein is also required for adaptation to growth at low temperatures.
Controlled proteolysis plays an essential role in the regulation of many cellular developmental processes, and it is therefore not surprising that most of the newly discovered components in the competence signal transduction network are somehow involved in this process. Mutations affecting the activity of the proteases concerned show very pleiotropic phenotypes. For example, in B. subtilis blocking the expression of the protease ClpP disturbs competence development, motility, degradative enzyme production and sporulation (Msadek et al., 1998). The absence of ClpP results in high levels of MecA. Since binding of MecA to ComK reduces the activity of ComK, high MecA levels will prevent development of competence, despite the absence of ClpP-dependent proteolyses of ComK. ClpP can also form an ATP-dependent protease complex with the chaperone ClpX, and a disruption of clpX interferes with the development of competence as well. In such a mutant the expression of comS appears to be insufficient to prevent the MecA-mediated degradation of ComK. A disruption in a gene called spx suppresses the adverse effects of clpP or clpX mutations (Nakano et al., 2002
). Protein-binding studies indicated that Spx forms a complex with MecA and ClpCP, and enhances the binding of ComK to this protein complex. As a result, higher concentrations of ComS are required to release ComK from the complex and prevent the proteolytic degradation of ComK. The role of Spx in the competence signal transduction cascade is unclear. A disruption of spx has no consequence for the development of competence, and expression of spx is very low under wild-type conditions. It is only when ClpP or ClpX is absent that Spx reaches levels high enough to obstruct the activity of ComS.
Due to the general use of ATP-dependent proteases in so many cellular processes, substrate interference can be an important factor in gene regulation. An example which illustrates this phenomenon is the MecA paralogue YpbH. When the concentration of YpbH is disturbed in the cell, the expression of comK changes, since YpbH binds to ClpC as well (Persuh et al., 2002).
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Further intertwinement of the regulation circuitry |
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The main pathways of the competence signal transduction cascade are depicted in Fig. 2 with black lines. However, this scheme remains a simplification, as the different regulatory pathways are not separate entities but are mutually intertwined. A few examples have already be mentioned, such as sigma-H, which is required for the expression of phosphorelay components and PhrC. Yet many more cross-links in the regulation circuitry of Fig. 2
can be drawn (grey lines). For instance, ClpX influences sigma-H activity (Liu et al., 1999
), high concentrations of phosphorylated DegU reduce srfA transcription (Hahn & Dubnau, 1991
), SinR is a repressor of the spo0A promoter (Mandic-Mulec et al., 1995
), and also represses rok expression (Hoa et al., 2002
), and CodY exerts its repressive action on both comK and srfA transcription (Serror & Sonenshein, 1996
). AbrB negatively controls, apart from comK transcription (Hahn et al., 1995a
), the production of PhrC (Solomon et al., 1995
), and expression of spo0H (Weir et al., 1991
) and rok (Hoa et al., 2002
), whereas Spo0A represses abrB, but stimulates expression of sinI (Gaur et al., 1988
). Finally, the quorum-sensing pathway gets increasingly complicated in view of the observation that several rap/phr operons, including rapA/phrA and rapC/phrC, are also regulated by the ComP/ComA two-component system (Lazazzera et al., 1999
; Perego et al., 1996
).
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Conclusions |
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It is remarkable that, for a radical differentiation process like competence, B. subtilis uses almost no regulatory proteins that are exclusively used in this process. For several years the ComS/MecA/ComK regulation pathway was considered to be solely involved in competence regulation. However, it was shown later that a mecA-null mutation inhibits expression of sigma-D, the sigma factor involved in motility and chemotaxis, and that this inhibition partially depended on ComK (Liu & Zuber, 1998; Rashid et al., 1996
). Competence is not unusual in having almost no unique private regulators at its disposal. In fact, the various stationary-phase processes in B. subtilis share the majority of their regulators. A strong interlock between gene regulatory pathways appears to be a common fact among prokaryotes. Looking at the regulation of general adaptive processes in bacteria, such as catabolite repression, and heat- and cold-shock response, it is apparent that the regulation cascades are composed of many general pleiotropic regulatory proteins. So is there an evolutionary advantage of interlocking gene regulatory pathways? Efficiency might be the key to this question. Because various transcriptional regulators, depending on where they bind a promoter, can function positively as well as negatively, the use of shared regulators is an efficient mechanism for coordinating and discriminating between different cellular responses. It links regulatory pathways and as such ensures a tight coordination between them. In addition, cells need lesser regulatory proteins as a result of which they handle their metabolic resources more economically.
The phenomenon of interlocked gene regulatory circuits has also been related to stability and robustness of the system (Little et al., 1999). A stable network will maintain its state in the face of small perturbations (stochastic fluctuations) of input signals and network components. It has been suggested, and recently experimentally supported, that especially negative feedback loops provide such stability (Becskei & Serrano, 2000
). Negative feedback loops are commonly present in complex gene regulatory circuits. In this review, several examples have been described, yet, in case of competence development it is questionable whether stability is an important reason for the intertwinement of the gene regulatory pathways. The experience with competence development in B. subtilis teaches that the fraction of cells which ultimately become competent fluctuates considerably, despite use of carefully controlled growth conditions.
Robustness of gene regulatory circuits refers to the sensitivity of systems towards changes in the biochemical parameters of the components brought about by genetic alterations of the components (Little et al., 1999). Particularly in organisms with an active and promiscuous genetic exchange system, such as genetic competence in B. subtilis, it can be envisioned that robustness of gene regulatory circuits is vital.
The full measure of complexity of gene regulation networks complicates the ascertainment of properties such as stability and robustness. The rise of whole-genome transcription measurements with DNA arrays, and developments in high-throughput two-hybrid analyses, makes it possible to study these phenomena at a new level. Several in silico modelling studies with extensive gene regulation networks, based on transcriptome and proteome data from yeast, provided evidence that connectivity increases the stability and robustness of gene regulation networks (Featherstone & Broadie, 2002; Maslov & Sneppen, 2002
; Wagner, 2000
). In the near future, such in silico studies will be achievable with B. subtilis and other prokaryotes. By then it will be interesting to examine whether the competence signal transduction network is more stable than gene regulation networks of bacteria which live in stable environments, or more robust than gene regulation networks of bacteria which do not become genetically competent.
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ACKNOWLEDGEMENTS |
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