Reversible activation of a transcription factor by methionine oxidation

Oxidative stress is caused by the accumulation of reactive oxygen species, which damage macromolecules and harm cells. The reactive oxygen species hypochlorite is produced by the immune system to kill invading microorganisms by damaging and oxidizing proteins preferentially at the sulfur in cysteine and methionine residues. Methionine oxidation has been reported to inactivate proteins but no regulatory role in a reversible activation mechanism has been described to date. Here, we show evidence that an oxidative stress transcription factor is regulated by reversible methionine oxidation. Activation in hypochlorite-stressed cells is mediated by oxidation of conserved methionines to methionine sulfoxide that results in strong DNA binding. Inactivation is accomplished by the methionine sulfoxide reductases MsrA and MsrB, which reduce methionine sulfoxide back to methionine and alleviate binding to the target promoter. Thus, by employing the typically inactivating methionine oxidation to gain activity, the transcription factor is perfectly suited to protect cells from hypochlorite stress.