2010 Anne A. Johnson Work Awardee. Abstract: Proteolytic control is essential for protein homeostasis and for modulating the levels of specific regulatory factors. Adaptor proteins can accelerate proteolysis by recognizing specific substrates and delivering or tethering them to the complex that catalyzes protein degradation. One regulatory factor that is under adaptor-mediated proteolytic control is Spx, a global transcriptional regulator of the oxidative stress response in Gram-positive bacteria. Its activity has been linked to virulence in Streptococci, Listeria, and Staphylococcus. Spx concentration is elevated when cells undergo oxidative stress. When stress is alleviated, Spx, which is growth restricting at high concentrations, is rapidly degraded by the ATP-dependent protease, ClpXP. Proteolysis is accelerated by the substrate recognition factor, YjbH, which serves the role of an adaptor in ClpXP-catalyzed Spx degradation. Using Bacillus subtilis as a gram-positive model, we are investigating the mechanism of YjbH-mediated proteolytic control of Spx concentration. Our recent studies showed that YjbH binds directly to Spx and that the C-terminus of Spx is important for YjbH recognition; removal of the C-terminal 12 residues results in elevated Spx concentration and activity. Another level of regulation was uncovered with the discovery of YirB, a small peptide that elevates Spx concentration by directly inhibiting YjbH.