Legionella metaeffector MavL reverses ubiquitin ADP-ribosylation via a conserved arginine-specific macrodomain

Zhengrui Zhang, Jiaqi Fu, Johannes Gregor Matthias Rack, Chuang Li, Jim Voorneveld, Dmitri V. Filippov, Ivan Ahel, Zhao-Qing Luo and Chittaranjan Das ()
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Zhengrui Zhang: Purdue University
Jiaqi Fu: Purdue University
Johannes Gregor Matthias Rack: University of Oxford
Chuang Li: Purdue University
Jim Voorneveld: Leiden University
Dmitri V. Filippov: Leiden University
Ivan Ahel: University of Oxford
Zhao-Qing Luo: Purdue University
Chittaranjan Das: Purdue University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract ADP-ribosylation is a reversible post-translational modification involved in various cellular activities. Removal of ADP-ribosylation requires (ADP-ribosyl)hydrolases, with macrodomain enzymes being a major family in this category. The pathogen Legionella pneumophila mediates atypical ubiquitination of host targets using the SidE effector family in a process that involves ubiquitin ADP-ribosylation on arginine 42 as an obligatory step. Here, we show that the Legionella macrodomain effector MavL regulates this pathway by reversing the arginine ADP-ribosylation, likely to minimize potential detrimental effects caused by the modified ubiquitin. We determine the crystal structure of ADP-ribose-bound MavL, providing structural insights into recognition of the ADP-ribosyl group and catalytic mechanism of its removal. Further analyses reveal DUF4804 as a class of MavL-like macrodomain enzymes whose representative members show unique selectivity for mono-ADP-ribosylated arginine residue in synthetic substrates. We find such enzymes are also present in eukaryotes, as exemplified by two previously uncharacterized (ADP-ribosyl)hydrolases in Drosophila melanogaster. Crystal structures of several proteins in this class provide insights into arginine specificity and a shared mode of ADP-ribose interaction distinct from previously characterized macrodomains. Collectively, our study reveals a new regulatory layer of SidE-catalyzed ubiquitination and expands the current understanding of macrodomain enzymes.

Date: 2024
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DOI: 10.1038/s41467-024-46649-2

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