Microbiology Poised by Noise

Annalisa M. VanHook

Science, AAAS, Washington, DC 20005, USA

Bacterial sigma factors confer promoter specificity to the RNA polymerase holoenzyme, with primary sigma factors being responsible for regulating expression of housekeeping genes and alternative sigma factors stimulating transcription of genes associated with specific regulatory programs, such as the response to starvation or heat shock. In response to environmental or energy stresses, bacteria such as Bacillus subtilis initiate production of the alternative sigma factor ^B, which stimulates the transcription of various target genes associated with pathogenicity. ^B activity is repressed by the kinase and anti-sigma factor RsbW and activated by the unphosphorylated form of the anti-anti-sigma factor RsbV. The phosphorylation status of RsbV is controlled by RsbW and the phosphatase RsbQP. Using a ^B-responsive fluorescent reporter, Locke et al. observed that Bacillus cultures exhibited sporadic, unsynchronized pulses of ^B activity in response to constant exposure to the energy stressor mycophenolic acid (MPA). Increasing the concentration of MPA caused an increase in the frequency of pulses but had little effect on the amplitude or duration of pulses. In a strain of Bacillus that forms multinucleate filaments in which cells share a common cytoplasm through which cellular contents freely diffuse, the frequency of MPA-induced pulses of ^B activity decreased, thus suggesting that noise resulting from cell-to-cell differences in the abundance of circuit components played a role in pulse generation. Pulse frequency was especially sensitive to the abundance of RsbQP and RsbW, and MPA treatment induced an increase in RsbQP abundance. Initial ^B pulses were subject to a mixed feedback loop in which ^B activity was first amplified by a positive transcriptional feedback mechanism until the abundance of RsbW exceeded that of RsbQP to terminate the pulse. ^B activity inhibits growth but allows cells to respond to stress, so this system provides a means by which variability in the population ensures its survival. The core of the ^B circuit is conserved across diverse bacterial species, and other alternative sigma factors engage similar genetic circuits, suggesting that this type of mechanism utilizing stochastic pulses of activity may be widely used to respond to unpredictable environmental conditions.

J. C. W. Locke, J. W. Young, M. Fontes, M. J. H. Jiménez, M. B. Elowitz, Stochastic pulse regulation in bacterial stress response. Science 334, 366–369 (2011). [Abstract] [Full Text]

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