Activation of Toxin-Antitoxin System Toxins Suppresses Lethality Caused by the Loss of σE in Escherichia coli

sigma(E), an alternative sigma factor that governs a major signaling pathway in envelope stress responses in Gram-negative bacteria, is essential for growth of Escherichia coli not only under stressful conditions, such as elevated temperature, but also under normal laboratory conditions. A mutational inactivation of the hicB gene has been reported to suppress the lethality caused by the loss of sigma(E). hicB encodes the antitoxin of the HicA-HicB toxin-antitoxin (TA) system; overexpression of the HicA toxin, which exhibits mRNA interferase activity, causes cleavage of mRNAs and an arrest of cell growth, while simultaneous expression of HicB neutralizes the toxic effects of overproduced HicA. To date, however, how the loss of HicB rescues the cell lethality in the absence of sigma(E) and, more specifically, whether HicA is involved in this process remain unknown. Here we showed that simultaneous disruption of hicA abolished suppression of the sigma(E) essentiality in the absence of hicB, while ectopic expression of wild-type HicA, but not that of its mutant forms without mRNA interferase activity, restored the suppression. Furthermore, HicA and two other mRNA interferase toxins, HigB and YafQ, suppressed the sigma(E) essentiality even in the presence of chromosomally encoded cognate antitoxins when these toxins were overexpressed individually. Interestingly, when the growth media were supplemented with low levels of antibiotics that are known to activate toxins, E. coli cells with no suppressor mutations grew independently of sigma(E). Taken together, our results indicate that the activation of TA system toxins can suppress the sigma(E) essentiality and affect the extracytoplasmic stress responses. IMPORTANCE sigma(E) is an alternative sigma factor involved in extracytoplasmic stress responses. Unlike other alternative sigma factors, sigma(E) is indispensable for the survival of E. coli even under unstressed conditions, although the exact reason for its essentiality remains unknown. Toxin-antitoxin (TA) systems are widely distributed in prokaryotes and are composed of two adjacent genes, encoding a toxin that exerts harmful effects on the toxin-producing bacterium itself and an antitoxin that neutralizes the cognate toxin. Curiously, it is known that inactivation of an antitoxin rescues the sigma(E) essentiality, suggesting a connection between TA systems and sigma(E) function. We demonstrate here that toxin activation is necessary for this rescue and suggest the possible involvement of TA systems in extracytoplasmic stress responses.