Abstract
Normal cellular processes give rise to toxic metabolites that cells must mitigate. Formaldehyde is a universal stressor and potent metabolic toxin that is generated in organisms from bacteria to humans. Methylotrophic bacteria such as Methylorubrum extorquens face an acute challenge due to their production of formaldehyde as an obligate central intermediate of single-carbon metabolism. Mechanisms to sense and respond to formaldehyde were speculated to exist in methylotrophs for decades but had never been discovered. Here, we identify a member of the DUF336 domain family, named efgA for enhanced formaldehyde growth, that plays an important role in endogenous formaldehyde stress response in M. extorquens PA1 and is found almost exclusively in methylotrophic taxa. Our experimental analyses reveal that EfgA is a formaldehyde sensor that rapidly arrests growth in response to elevated levels of formaldehyde. Heterologous expression of EfgA in Escherichia coli increases formaldehyde resistance, indicating that its interaction partners are widespread and conserved. EfgA represents the first example of a formaldehyde stress response system that does not involve enzymatic detoxification. Thus, EfgA comprises a unique stress response mechanism in bacteria, whereby a single protein directly senses elevated levels of a toxic intracellular metabolite and safeguards cells from potential damage.
Highlights
Robust organisms “maintain performance in the face of perturbations and uncertainty” [1] and require mechanisms for averting cellular damage during stress
During exponential growth on succinate, we found that Δfae mutants accumulated internal formaldehyde when treated with 1 mM methanol, confirming that disrupting the dH4MPT pathway is correlated to an increase in intracellular formaldehyde (S17 Fig)
Formaldehyde detoxification systems have been identified in all domains of life [106]
Summary
Robust organisms “maintain performance in the face of perturbations and uncertainty” [1] and require mechanisms for averting cellular damage during stress. The response systems that mitigate these endogenous stressors vary from detoxification systems, to neutralize reactive compounds such as hydrogen peroxide, imines, and aldehydes [2,3,4,5], to post-damage repair systems such as enzyme-mediated damage reversal [6,7] and targeted molecular degradation systems [8]. Induction of these responses can arise due to direct sensing of the metabolic toxins [9] or by sensing the damaged molecules themselves [6]. There is a single example of a formaldehyde sensor, FrmR, a transcriptional repressor that directly binds formaldehyde and controls expression of the detoxification pathway in Escherichia coli [19]
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