LAUSR

Significance Mitochondria are organelles of the central metabolism that produce ATP and play fundamental roles in eukaryotic cell function and thereby become targets for pathogenic bacteria to manipulate. We found that the intracellular bacterial pathogen, Legionella pneumophila, targets mitochondrial ADP/ATP translocases (ANTs), the function of which is linked to the mitochondrial ATP synthesis. This is achieved by a pair of effector proteins, Lpg0080 and Lpg0081, which have opposing enzymatic activities as an ADP ribosyltransferase (ART) and an ADP ribosylhydrolase (ARH), respectively, coordinately regulating the chemical modification of ANTs upon infection. Our structural analyses indicate that Lpg0081 is an ARH with a noncanonical macrodomain, whose folding topology is distinct from that of the canonical macrodomain of known eukaryotic, archaeal, and bacterial proteins.