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

• Published in: Molecular cell Vol. 59; no. 2; pp. 309 - 320
• Main Authors: Rack, Johannes Gregor Matthias, Morra, Rosa, Barkauskaite, Eva, Kraehenbuehl, Rolf, Ariza, Antonio, Qu, Yue, Ortmayer, Mary, Leidecker, Orsolya, Cameron, David R., Matic, Ivan, Peleg, Anton Y., Leys, David, Traven, Ana, Ahel, Ivan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.07.2015; Cell Press
• Subjects: Adenosine Diphosphate Ribose - metabolism; Bacterial Proteins - chemistry; Bacterial Proteins - classification; Bacterial Proteins - genetics; Catalytic Domain; Crystallography, X-Ray; Genes, Bacterial; HEK293 Cells; Host-Pathogen Interactions; Humans; Lactobacillales - enzymology; Lactobacillales - genetics; Lipoylation; Models, Molecular; Operon; Oxidative Stress; Phylogeny; Protein Conformation; Sirtuins - chemistry; Sirtuins - classification; Sirtuins - genetics; Staphylococcus aureus - enzymology; Staphylococcus aureus - genetics; Staphylococcus aureus - pathogenicity; Streptococcus pyogenes - enzymology; Streptococcus pyogenes - genetics; Streptococcus pyogenes - pathogenicity
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2015.06.013

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. [Display omitted] •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.