Identification of a Class of Protein ADP-Ribosylating Sirtuins in Microbial Pathogens

• DOI: 10.1016/j.molcel.2015.06.013
• Publication Date: 2015-07-10T07:43:01Z
• Authors: Johannes Gregor M...; Rosa Morra; Eva Barkauskaite; Rolf Kraehenbuehl; Antonio Ariza; Yue Qu; Mary Ortmayer; Orsolya Leidecker; David R. Cameron; Ivan Matic; Anton Y. Peleg; David Leys; Ana Traven; Ivan Ahel
• Keywords: Models, Molecular; 0301 basic medicine; Adenosine Diphosphate Ribose; Staphylococcus aureus; Protein Conformation; Streptococcus pyogenes; Lipoylation; Cell Biology; Crystallography, X-Ray; Article; 3. Good health; Oxidative Stress; 03 medical and health sciences; HEK293 Cells; Bacterial Proteins; Genes, Bacterial; Lactobacillales; Catalytic Domain; Host-Pathogen Interactions; Operon; Humans; Sirtuins; Molecular Biology; Phylogeny

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.