Identification of a Class of Protein ADP-Ribosylating Sirtuins in Microbial Pathogens.
Rack JGM., Morra R., Barkauskaite E., Kraehenbuehl R., Ariza A., Qu Y., Ortmayer M., Leidecker O., Cameron DR., Matic I., Peleg AY., Leys D., Traven A., Ahel I.
Sirtuins are an ancient family of NAD(+)-dependent deacylases connected with the regulation of fundamental cellular processes including metabolic homeostasis and genome integrity. We show the existence of a hitherto unrecognized class of sirtuins, found predominantly in microbial pathogens. In contrast to earlier described classes, these sirtuins exhibit robust protein ADP-ribosylation activity. In our model organisms, Staphylococcus aureus and Streptococcus pyogenes, the activity is dependent on prior lipoylation of the target protein and can be reversed by a sirtuin-associated macrodomain protein. Together, our data describe a sirtuin-dependent reversible protein ADP-ribosylation system and establish a crosstalk between lipoylation and mono-ADP-ribosylation. We propose that these posttranslational modifications modulate microbial virulence by regulating the response to host-derived reactive oxygen species.