한빛사 논문
Tomoko Kuboria,b,1,2, Junyup Leec,1, Hyunmin Kimc,3, Kohei Yamazakia,4, Masanari Nishikawaa, Tomoe Kitaoa, Byung-Ha Ohc,2, and Hiroki Nagaia,b,2
aDepartment of Microbiology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan; bCenter for Highly Advanced Integration of Nano and Life Sciences, Gifu University, Gifu 501-1194, Japan; and cDepartment of Biological Sciences, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea
1T. Kubori and J.L. contributed equally to this work.
2To whom correspondence may be addressed.
3Present address: School of Biology, Institute of Molecular Biology and Genetics, Seoul National University, Seoul 08826, Republic of Korea.
4Present address: Laboratory of Veterinary Public Health, School of Veterinary Medicine, Kitasato University, Towada, Aomori 034-8628, Japan.
Abstract
Adenosine diphosphate (ADP) ribosylation is a reversible posttranslational modification involved in the regulation of numerous cellular processes. Prototype ADP ribosyltransferases (ARTs) from many pathogenic bacteria are known to function as toxins, while other bacterial ARTs have just recently emerged. Recent studies have shown that bacteria also possess enzymes that function as poly-ADP ribose (ADPr) glycohydrolases (PARGs), which reverse poly-ADP ribosylation. However, how bacteria manipulate host target proteins by coordinated reactions of ARTs and ADPr hydrolases (ARHs) remains elusive. The intracellular bacterial pathogen Legionella pneumophila, the causative agent of Legionnaires’ disease, transports a large array of effector proteins via the Dot/Icm type IV secretion system to host cells. The effector proteins, which mostly function as enzymes, modulate host cellular processes for the bacteria’s benefit. In this study, we identified a pair of L. pneumophila effector proteins, Lpg0080 and Lpg0081, which function as an ART and an ARH, respectively. The two proteins were shown to coordinately modulate mitochondrial ADP/adenosine triphosphate (ATP) translocases (ANTs) by their enzymatic activities to conjugate ADPr to, and remove it from, a key arginine residue. The crystal structures of Lpg0081 and the Lpg0081:ADPr complex indicated that Lpg0081 is a macroD-type ARH with a noncanonical macrodomain, whose folding topology is strikingly distinct from that of the canonical macrodomain that is ubiquitously found in eukaryotic PARGs and ARHs. Our results illustrate that L. pneumophila has acquired an effector pair that coordinately manipulate mitochondrial activity via reversible chemical modification of ANTs.
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