title: Proteolytic regulation of toxin-antitoxin systems by ClpPC in Staphylococcus aureus.
abstract: Bacterial toxin-antitoxin (TA) systems typically consist of a small, labile antitoxin that inactivates a specific longer-lived toxin. In Escherichia coli, such antitoxins are proteolytically regulated by the ATP-dependent proteases Lon and ClpP. Under normal conditions, antitoxin synthesis is sufficient to replace this loss from proteolysis, and the bacterium remains protected from the toxin. However, if TA production is interrupted, antitoxin levels decrease, and the cognate toxin is free to inhibit the specific cellular component, such as mRNA, DnaB, or gyrase. To date, antitoxin degradation has been studied only in E. coli, so it remains unclear whether similar mechanisms of regulation exist in other organisms. To address this, we followed antitoxin levels over time for the three known TA systems of the major human pathogen Staphylococcus aureus, mazEF, axe1-txe1, and axe2-txe2. We observed that the antitoxins of these systems, MazE(sa), Axe1, and Axe2, respectively, were all degraded rapidly (half-life [t(1/2)], approximately 18 min) at rates notably higher than those of their E. coli counterparts, such as MazE (t(1/2), approximately 30 to 60 min). Furthermore, when S. aureus strains deficient for various proteolytic systems were examined for changes in the half-lives of these antitoxins, only strains with clpC or clpP deletions showed increased stability of the molecules. From these studies, we concluded that ClpPC serves as the functional unit for the degradation of all known antitoxins in S. aureus.
authors.affiliation: Department of Microbiology and Immunology, Dartmouth Medical School, Hanover, NH 03755, USA.
authors.forename: Niles P
authors.initials: NP
authors.lastname: Donegan
authors.forename: Earl T
authors.initials: ET
authors.lastname: Thompson
authors.forename: Zhibiao
authors.initials: Z
authors.lastname: Fu
authors.forename: Ambrose L
authors.initials: AL
authors.lastname: Cheung
mesh_terms: D001426:Bacterial Proteins / Q000378:metabolism*; D001427:Bacterial Toxins / Q000378:metabolism*; D049071:Endopeptidase Clp / Q000172:deficiency / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D055786:Gene Knockout Techniques; D006207:Half-Life; D006360:Heat-Shock Proteins / Q000172:deficiency / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000502:physiology*
chemical_list: D001426:Bacterial Proteins; D001427:Bacterial Toxins; C087481:ClpC protein, Bacteria; D006360:Heat-Shock Proteins; C540055:MazE protein, Staphylococcus aureus; D049071:Endopeptidase Clp