The disulfide bond formation (DSB) system: so much more than a housekeeper

Disulfide bonds are covalent linkages connecting two cysteine residues. When formed within the same polypeptide, they assist protein folding and enhance protein stability. In principle, disulfide formation could be facilitated by ubiquitous small-molecule oxidants, like oxygen. Instead, it is catalyzed by dedicated oxidative protein folding pathways throughout the tree of life. In bacteria, disulfides are abundant outside the cytoplasm, whereby chemical and mechanical stresses take their toll on protein molecules. The Disulfide Bond Formation (DSB) system in Escherichia coli K-12 has served as the paradigm for bacterial disulfide bond formation and has been, largely, considered a proteome housekeeper. In this article we discuss the central role of the DSB system for protein homeostasis, the unprecedented diversity of DSB proteins across the bacterial phylogeny, and their emerging roles in infectious disease. We also propose that beyond the known uses of DSB components in biotechnology, the DSB system offers promising avenues for the development of next-generation strategies against challenging bacterial pathogens.