How specific is the role of hipA in persister generation?

The toxin-antitoxin (TA) system, found in the plasmids and chromosomes of many bacteria, is implicated in persister formation. This system consists of a pair of genes, one of which encodes a stable toxin and the other of which encodes an unstable antitoxin. Examples for such systems include hipBA, relBE, mazEF etc. In the presence of the antitoxin, the expression of the toxin, which inhibits translation, is down regulated. However, when the antitoxin level is reduced, the expression of the toxin becomes predominant, resulting in the inhibition of translation and thus the protein synthesis that finally results in programmed cell death (PCD).

The major TA system involved in persister cell formation is hipBA. Mutations in hipA produce a high frequency of persisters (Moyed and Bertrand 1983). Similarly, overexpression of HipA results in 10-to-1000 fold increases in persister formation (Falla and Chopra 1998; Keren et al. 2004; Korch and Hill 2006). In addition, overexpression of RelE, the toxin protein of another TA system, also results in a high frequency of persisters (Keren et al. 2004). Thus, specific roles for these toxins in persister formation were proposed.

However, the importance of TA modules in persister formation is questioned by some researchers. Vazquez-Laslop et al. (2006) found that the cells overexpressing proteins unrelated to TA modules, also resulted in a high frequency of persisters. They found that the proteins that are toxic to the cell, when overexpressed, would result in a high frequency of persisters, thus questioning the specific roles of hipA or other TA modules in persister generation. This raises the question whether the in vitro over-expression of proteins is a reliable method to demonstrate the phenotypic shift of persisters.

Falla, T. J., and Chopra, I. (1998). Joint tolerance to beta-lactam and fluoroquinolone antibiotics in Escherichia coli results from overexpression of hipA. Antimicrob Agents Chemother 42(12), 3282-4.

Keren et al. (2004). Persister cells and tolerance to antimicrobials. FEMS Microbiol Lett 230(1), 13-8.

Korch, S. B., and Hill, T. M. (2006). Ectopic overexpression of wild-type and mutant hipA genes in Escherichia coli: effects on macromolecular synthesis and persister formation. J Bacteriol 188(11), 3826-36.

Moyed, H. S., and Bertrand, K. P. (1983). hipA, a newly recognized gene of Escherichia coli K-12 that affects frequency of persistence after inhibition of murein synthesis. J Bacteriol 155(2), 768-75.

Vazquez-Laslop et al. (2006). Increased persistence in Escherichia coli caused by controlled expression of toxins or other unrelated proteins. J Bacteriol 188(10), 3494-7.