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The SoxRS response of Escherichia coli is directly activated by redox-cycling drugs rather than by superoxide.
Mol Microbiol. 2011 Mar; 79(5):1136-50
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25 Jan 2011
DOI: 10.3410/f.7857957.8204056
This interesting paper sheds new light on the bacterial SoxRS response, and adds to the growing body of literature suggesting that superoxide is not the physiological oxidant for the [Fe-S]-containing SoxR protein. Rather, it is shown that SoxR mediates a response to redox-active compounds, and that these...Continue reading
This interesting paper sheds new light on the bacterial SoxRS response, and adds to the growing body of literature suggesting that superoxide is not the physiological oxidant for the [Fe-S]-containing SoxR protein. Rather, it is shown that SoxR mediates a response to redox-active compounds, and that these compounds oxidize SoxR directly.
SoxR is a transcriptional regulator containing a [2Fe-2S] cluster that, in Escherichia coli, activates expression of the soxS gene. SoxS is itself a transcriptional regulator that activates the >100 genes belonging to the SoxRS regulon. In some other bacteria, there is no SoxS, and so SoxR activates the target genes directly. The SoxRS regulon is induced by redox cycling compounds that, in the presence of oxygen, cause the intracellular accumulation of superoxide. This treatment results in oxidation of the [Fe-S] cluster of SoxR, and concomitant activation of the protein. Thus, a dogma has developed in which the physiological oxidant for SoxR is superoxide. But this reaction has never been demonstrated biochemically, and several observations in the literature are not consistent with the model. For example, the SoxRS regulon can be induced by redox cycling compounds in anaerobic cultures supplied with a respiratory electron acceptor (such as nitrate), conditions which preclude the formation of superoxide.
In this new paper from the Imlay lab, in vivo experiments demonstrate that superoxide is not the physiological signal for activation of SoxR, which is instead proposed to respond directly to redox active compounds. Accordingly, it is shown that such compounds can oxidize SoxR directly in vitro (in the absence of oxygen), while the rate of oxidation of SoxR by superoxide is too slow to be physiologically relevant. A model is developed in which redox active compounds oxidize SoxR directly (becoming reduced in the process), and are then re-oxidized by electron transfer to the quinone pool (explaining the requirement for an electron acceptor such as oxygen or nitrate for robust SoxR activation).
This model provides a satisfying rationale for the fact that the SoxR(S) regulon typically includes genes encoding drug efflux systems and, in some organisms, does not include genes encoding enzymes that might directly counteract superoxide (i.e. superoxide dismutase). Thus, the main role of SoxR may be to counter the toxic effects of redox active compounds, which are excreted by some organisms, perhaps to inhibit the growth of competitors. The authors do not discuss how this new model can be reconciled with a recent suggestion that DNA-bound SoxR can be activated by guanine radicals resulting from oxidative stress {1}.
SoxR is a transcriptional regulator containing a [2Fe-2S] cluster that, in Escherichia coli, activates expression of the soxS gene. SoxS is itself a transcriptional regulator that activates the >100 genes belonging to the SoxRS regulon. In some other bacteria, there is no SoxS, and so SoxR activates the target genes directly. The SoxRS regulon is induced by redox cycling compounds that, in the presence of oxygen, cause the intracellular accumulation of superoxide. This treatment results in oxidation of the [Fe-S] cluster of SoxR, and concomitant activation of the protein. Thus, a dogma has developed in which the physiological oxidant for SoxR is superoxide. But this reaction has never been demonstrated biochemically, and several observations in the literature are not consistent with the model. For example, the SoxRS regulon can be induced by redox cycling compounds in anaerobic cultures supplied with a respiratory electron acceptor (such as nitrate), conditions which preclude the formation of superoxide.
In this new paper from the Imlay lab, in vivo experiments demonstrate that superoxide is not the physiological signal for activation of SoxR, which is instead proposed to respond directly to redox active compounds. Accordingly, it is shown that such compounds can oxidize SoxR directly in vitro (in the absence of oxygen), while the rate of oxidation of SoxR by superoxide is too slow to be physiologically relevant. A model is developed in which redox active compounds oxidize SoxR directly (becoming reduced in the process), and are then re-oxidized by electron transfer to the quinone pool (explaining the requirement for an electron acceptor such as oxygen or nitrate for robust SoxR activation).
This model provides a satisfying rationale for the fact that the SoxR(S) regulon typically includes genes encoding drug efflux systems and, in some organisms, does not include genes encoding enzymes that might directly counteract superoxide (i.e. superoxide dismutase). Thus, the main role of SoxR may be to counter the toxic effects of redox active compounds, which are excreted by some organisms, perhaps to inhibit the growth of competitors. The authors do not discuss how this new model can be reconciled with a recent suggestion that DNA-bound SoxR can be activated by guanine radicals resulting from oxidative stress {1}.
References
1.
DNA-mediated redox signaling for transcriptional activation of SoxR.
Proc Natl Acad Sci USA 2009 Aug 11; 32(106):13164-8
PMID: 19651620
Disclosures
None declared
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Spiro S: F1000Prime Recommendation of [Gu M and Imlay JA, Mol Microbiol 2011, 79(5):1136-50]. In F1000Prime, 25 Jan 2011; DOI: 10.3410/f.7857957.8204056. F1000Prime.com/7857957#eval8204056
F1000Prime Recommendations, Dissents and Comments for [Gu M and Imlay JA, Mol Microbiol 2011, 79(5):1136-50]. In F1000Prime, 23 May 2013; F1000Prime.com/7857957
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When Escherichia coli is exposed to redox-cycling drugs, its SoxR transcription factor is activated by oxidation of its [2Fe-2S] cluster. In aerobic cells these drugs generate superoxide, and because superoxide dismutase (SOD) is a member of the SoxRS regulon, superoxide was initially thought to be the activator of SoxR. Its many-gene regulon was therefore believed to comprise a defence against superoxide stress. However, we found that abundant superoxide did not effectively activate SoxR in an SODā» mutant, that overproduced SOD could not suppress activation by redox-cycling drugs, and that redox-cycling drugs were able to activate SoxR in anaerobic cells as long as alternative respiratory acceptors were provided. Thus superoxide is not the signal that SoxR senses. Indeed, redox-cycling drugs directly oxidized the cluster of purified SoxR in vitro, while superoxide did not. Redox-cycling drugs are excreted by both bacteria and plants. Their toxicity does not require superoxide, as they poisoned E. coli under anaerobic conditions, in part by oxidizing dehydratase iron-sulfur clusters. Under these conditions SoxRS induction was protective. Thus it is physiologically appropriate that the SoxR protein directly senses redox-cycling drugs rather than superoxide.
DOI: 10.1111/j.1365-2958.2010.07520.x
PMID: 21226770
