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Free keywords:
Adenosine Diphosphate Ribose/*metabolism
Bacterial Proteins/chemistry/*classification/genetics
Catalytic Domain
Crystallography, X-Ray
Genes, Bacterial
HEK293 Cells
Host-Pathogen Interactions
Humans
Lactobacillales/enzymology/genetics
Lipoylation
Models, Molecular
Operon
Oxidative Stress
Phylogeny
Protein Conformation
Sirtuins/chemistry/*classification/genetics
Staphylococcus aureus/enzymology/genetics/pathogenicity
Streptococcus pyogenes/enzymology/genetics/pathogenicity
Abstract:
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.
