Proposed model for TrfA regulation and activity in S. aureus. The adaptor TrfA associates with ClpCP to selectively degrade SsrA-tagged proteins and class II antitoxins, such as MazEsa. TrfA is itself degraded by ClpCP, which gives TrfA temporal nuance. The transcription of trfA is initiated from three upstream promoters, at least one of which is positively regulated by Spx. Spx activity is controlled by the degradation of the Spx protein via ClpXP and YjbH under normal conditions and with decreased proteolysis during oxidative, thiol, or antibiotic stress. Spx represses its own distal P1 promoter, creating a negative-feedback loop where less spx is transcribed during such stresses. X, ClpX; P, ClpP; C, ClpC.