Defensins are short cysteine-rich peptides that can inactivate bacterial toxins, but the mechanism by which they induce such inactivation has remained unclear. In Immunity, Kudryashova et al. show that the human neutrophil α-defensin HNP1 induces the unfolding of bacterial toxins, which results in the exposure of hydrophobic protein regions and instability, enhanced susceptibility to proteolysis, precipitation and functional inactivation. HNP1 inhibits the normal autoprocessing and increases the susceptibility of susceptible toxins, such as the Martx toxin from Vibrio cholerae, to proteolysis, but not that of mammalian enzymes or non-susceptible bacterial toxins. Binding of HNP1 to Martx induces unfolding and conformational changes in the tertiary and secondary structure of the toxin but not that of the defensin. These effects operate at normal physiological concentrations of salt and defensins and are shared by other defensins assessed, which suggests they represent a shared mechanism.

Immunity 41, 709–721 (2014)