Summary 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.
Graphical Abstract
Highlights • A class of sirtuins (SirTMs) is identified in microbial pathogens • SirTMs are linked to macrodomains and act as protein ADP-ribosyltransferases • Protein ADP-ribosylation by SirTMs is strictly lipoylation dependent and reversible • SirTMs modulate the response to oxidative stress
Oxidative stress has been recognized as a critical factor in human disease, aging, and the immune system function. Rack et al. report a structural and biochemical analysis of a sirtuin/macrodomain system modulating the oxidative stress response in pathogenic microorganisms via reversible protein ADP-ribosylation.