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Review
. 2020 Sep 15:11:1761.
doi: 10.3389/fmicb.2020.01761. eCollection 2020.

The Stress-Responsive Alternative Sigma Factor SigB of Bacillus subtilis and Its Relatives: An Old Friend With New Functions

Facundo Rodriguez Ayala  1   2 , Marco Bartolini  2   3 , Roberto Grau  2   3
Affiliations
Review

The Stress-Responsive Alternative Sigma Factor SigB of Bacillus subtilis and Its Relatives: An Old Friend With New Functions

Facundo Rodriguez Ayala et al. Front Microbiol. .

Abstract

Alternative sigma factors have led the core RNA polymerase (RNAP) to recognize different sets of promoters to those recognized by the housekeeping sigma A-directed RNAP. This change in RNAP promoter selectivity allows a rapid and flexible reformulation of the genetic program to face environmental and metabolic stimuli that could compromise bacterial fitness. The model bacterium Bacillus subtilis constitutes a matchless living system in the study of the role of alternative sigma factors in gene regulation and physiology. SigB from B. subtilis was the first alternative sigma factor described in bacteria. Studies of SigB during the last 40 years have shown that it controls a genetic universe of more than 150 genes playing crucial roles in stress response, adaption, and survival. Activation of SigB relies on three separate pathways that specifically respond to energy, environmental, and low temperature stresses. SigB homologs, present in other Gram-positive bacteria, also play important roles in virulence against mammals. Interestingly, during recent years, other unexpected B. subtilis responses were found to be controlled by SigB. In particular, SigB controls the efficiencies of spore and biofilm formation, two important features that play critical roles in adaptation and survival in planktonic and sessile B. subtilis communities. In B. subtilis, SigB induces the expression of the Spo0E aspartyl-phosphatase, which is responsible for the blockage of sporulation initiation. The upregulated activity of Spo0E connects the two predominant adaptive pathways (i.e., sporulation and stress response) present in B. subtilis. In addition, the RsbP serine-phosphatase, belonging to the energy stress arm of the SigB regulatory cascade, controls the expression of the key transcription factor SinR to decide whether cells residing in the biofilm remain in and maintain biofilm growth or scape to colonize new niches through biofilm dispersal. SigB also intervenes in the recognition of and response to surrounding microorganisms, a new SigB role that could have an agronomic impact. SigB is induced when B. subtilis is confronted with phytopathogenic fungi (e.g., Fusarium verticillioides) and halts fungal growth to the benefit of plant growth. In this article, we update and review literature on the different regulatory networks that control the activation of SigB and the new roles that have been described the recent years.

Keywords: Bacillus subtilis; SigB; alternative sigma factors; biocontrol; biofilm fitness; general stress response; sporulation.

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Figures

FIGURE 1
FIGURE 1
Bacillus subtilis responses to stress. There are two main and interconnected responses that B. subtilis uses to face stress. One response is the general stress response (GSR) triggered by many different types of stresses (for example environmental and energy-depleting stresses). The GSR is rapidly induced after 5–15 min, under laboratory-controlled conditions, it is reversible and depends on the activity of SigB (left part of the figure). This SigB-controlled response would be interpreted as a sort of “panic” and fast response that allows cells (either planktonic or sessile) to cope with multiple stresses. The second stress response (right part of the figure) is sporulation. This response ends with the formation of a mature, highly resistant, and long-lasting spore. Sporulation is time-consuming (at least 8 h to make a mature spore under laboratory-controlled conditions), it is tightly regulated at transcriptional and post-translational levels and responds to fewer stresses (mainly nutrient starvation). Sporulation is under the control of the phosphorelay that activates Spo0A by phosphorylation (i.e., Spo0A∼Pi formation). It is considered the last resort response that B. subtilis (and other bacilli) use to cope and survive under extreme, adverse conditions. Both responses, SigB- and Spo0A-controlled, are interconnected by the aspartyl phosphatase Spo0E induced by SigB. Spo0E inhibits sporulation because of the dephosphorylation of Spo0A∼Pi. In this sense, B. subtilis would be able to first explore less extreme alternatives (i.e., GSR induction) before to trigger the last resort strategy of survival that will end up in the formation of resistant and long-lasting spores. See the text for details.
FIGURE 2
FIGURE 2
Diagram of SigB regulatory pathways of general stress response under non-stress conditions in Bacillus subtilis. Under non-stress conditions the anti-anti-sigma factor RsbV (V, for simplicity) is phosphorylated (V∼P) by the kinase/anti-sigma factor RsbW (W, for simplicity). W captures SigB (σB) in a stable complex (W:σB), thereby preventing its binding to the RNA polymerase (RNAP). The PP2C-type phosphatase RsbU (U) is inactive. The serine threonine kinase RsbT (T) responsible for the activation of U is inactive and captured in the stressosome, also composed of the antagonist RsbS (S) and the putative sensor proteins RsbRA (RA), RsbRB (RB), RsbRC (RC), RsbRD (RD), and YtvA. Similarly, in the absence of energy stress, the PP2C-type phosphatase RsbP (P) and its activating protein RsbQ (Q) are inactive.
FIGURE 3
FIGURE 3
Diagram of SigB regulatory pathways of general stress response under stress conditions in Bacillus subtilis. Energy stress activates the PP2C-type phosphatase RsbP (P for simplicity) and the agonist protein RsbQ (Q for simplicity) which form a complex RsbQP (QP for simplicity) to dephosphorylate RsbV∼Pi (V∼P). Environmental stress induces the kinase activity of RsbT (T for simplicity) to phosphorylate RsbRA (RA∼P), RbsRB (RB∼P), and RsbS (S∼P). Released T from the stressosome binds and activates the PP2C-type phosphatase RsbU (U for simplicity) to dephosphorylate RsbV∼Pi (V∼P). Dephosphorylated RsbV (V), formed by the phosphatases P and/or U, binds to RsbW (W for simplicity), releasing SigB (σB) which in turn binds to RNAP and activates its target genes (i.e., GSR and spo0E). A third SigB activating pathway by low temperature stress operates independently of U, P, and V activities at the level of complex stability between RsbW and SigB (WσB). The RbsX phosphatase is responsible for the dephosphorylation of RsbRA∼Pi, RsbRB∼Pi, and RsbS∼Pi, to restore the levels of SigB activity to the ones present before stress (not shown for simplicity). See the text for further details.
FIGURE 4
FIGURE 4
Proposed model for the role of SigB on biofilm growth and fitness. (A) The general stress factor SigB is essential to stop the detrimental overgrowth of the mature biofilm and trigger dispersal before nutrient within the biofilm run out. The signal detected by SigB to accomplish these tasks is transduced through the RsbP/RsbQ energy-related route of the SigB regulatory cascade, which in turn positively upregulates the levels of SinR, the master negative and positive regulator of biofilm formation and motility in B. subtilis, respectively. The positive effect of SigB on spo0E expression would be responsible for the increased levels of SinR activity inside the mature biofilm. (B) Cells in SigB-deficient (ΔsigB) biofilms are unable to sense stress and maintain upregulated levels of SinR (spo0E is not induced) as the biofilm ages. As a consequence of such an energetic imbalance, the biofilm continued to grow and became larger but less resistant to aging and diverse stresses. Dispersal is also downregulated. Development of new drugs that negatively target SigB activity (SigB inhibition in dash lines) in bacterial pathogens of clinical relevance sharing with B. subtilis structural or functional homologs to SigB is an interesting line of research. See the text for details.
FIGURE 5
FIGURE 5
Antagonist response of B. subtilis confronted with the phytopathogen Fusarium verticillioides. The co-culture of a wild-type B. subtilis strain harboring a SigB-reporter gene fusion (ctc-lacZ) with F. verticillioides allows the observation of the antagonistic fungus-bacterium interaction. At the start of the co-incubation, 5 × 105 colony forming units (CFU) of fungal mycelia were poured at the center of the Petri dish, and 1 × 105 colony forming units (CFU) of a stationary phase culture of B. subtilis was placed at three different positions surrounding the fungus to better observe the antagonistic interaction. F. verticillioides-induced SigB activation is evidenced by blue color (derived from the expression of the ctc-lacZ fusion) in the borders of the B. subtilis biofilms (colonies) closer to the fungus. The areas represented by the green and pink rectangles correspond to the biofilm areas used to quantify the β-galactosidase activity (derived from the expressed ctc-lacZ fusion, blue color, inside the biofilm). The relative quantification of the β-galactosidase activity is shown as bar graphs. Microorganisms (B. subtilis and fungi) were co-incubated in PDA (Potato Dextrose Agar) plates at 28°C during 96 h before the photograph is taken.
FIGURE 6
FIGURE 6
Positive role of SigB in the biocontrol proficiency of PGPB B. subtilis. This cartoon summarizes the beneficial interaction between surfactin-producing B. subtilis cells and plants to resist phytopathogenic fungi. Biofilm- and surfactin-proficient B. subtilis cells can establish a beneficial biofilm at the plant rhizosphere and detect the fungal presence around them. The signal of fungal presence is transduced to the bacterium by an unknown signal that activates the energy stress pathway (PQ in the cartoon) of the SigB regulatory network. Active SigB increases the synthesis of the antifungal lipopeptide surfactin which is exported from the cell through the channel SwrC and/or free cellular membrane diffusion (not shown for simplicity). Outside the bacterial cells, surfactin exerts its fungal growth inhibitory effect. Additionally, surfactins have other two important properties. First, they are important molecules for the proficiency of bacilli at establishing robust and persistent beneficial biofilms at the plant rhizosphere, and second, they can induce plant systemic resistance (ISR) against pathogens. It has been reported that there is specific positive feedback (not shown in the figure for simplicity) from the plant to the bacterium, in which plant polysaccharides stimulate B. subtilis biofilm formation. See the text for details.
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