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

Zhang, Zhengrui; Fu, Jiaqi; Rack, Johannes Gregor Matthias; Li, Chuang; Voorneveld, Jim; Filippov, Dmitri V.; Ahel, Ivan; Luo, Zhao-Qing; Das, Chittaranjan

doi:10.1038/s41467-024-46649-2

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

Journal Article · 19 March 2024 · Nature Communications

DOI: https://doi.org/10.1038/s41467-024-46649-2 · OSTI ID:2470018

Zhang, Zhengrui ^[1];

^[1];

^[2]; Li, Chuang ^[1]; Voorneveld, Jim ^[3];

^[3];

^[2];

^[1];

^[1]

Purdue Univ., West Lafayette, IN (United States)
Univ. of Oxford (United Kingdom)
Leiden Univ. (Netherlands)

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States); SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2470018

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 15; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

References (69)

Molecular Tools for the Study of ADP‐Ribosylation: A Unified and Versatile Method to Synthesise Native Mono‐ADP‐Ribosylated Peptides Voorneveld, Jim; Rack, Johannes Gregor Matthias; van Gijlswijk, Luke Chemistry – A European Journal, Vol. 27, Issue 41 https://doi.org/10.1002/chem.202100337	journal	May 2021
Legionella pneumophila temporally regulates the activity of ADP/ATP translocases by reversible ADP‐ribosylation Fu, Jiaqi; Li, Pengwei; Guan, Hongxin mLife, Vol. 1, Issue 1 https://doi.org/10.1002/mlf2.12014	journal	March 2022
Using Dali for Protein Structure Comparison Holm, Liisa Methods in Molecular Biology https://doi.org/10.1007/978-1-0716-0270-6_3	book	January 2020
Cloning and site-directed mutagenesis of human ADP-ribosylarginine hydrolase. Takada, T.; Iida, K.; Moss, J. Journal of Biological Chemistry, Vol. 268, Issue 24 https://doi.org/10.1016/S0021-9258(17)46780-9	journal	August 1993
Chemistry-Based Functional Proteomics Reveals Novel Members of the Deubiquitinating Enzyme Family Borodovsky, Anna; Ovaa, Huib; Kolli, Nagamalleswari Chemistry & Biology, Vol. 9, Issue 10 https://doi.org/10.1016/S1074-5521(02)00248-X	journal	October 2002
Phosphoribosylation of Ubiquitin Promotes Serine Ubiquitination and Impairs Conventional Ubiquitination Bhogaraju, Sagar; Kalayil, Sissy; Liu, Yaobin Cell, Vol. 167, Issue 6 https://doi.org/10.1016/j.cell.2016.11.019	journal	December 2016
(ADP-ribosyl)hydrolases: Structural Basis for Differential Substrate Recognition and Inhibition Rack, Johannes Gregor Matthias; Ariza, Antonio; Drown, Bryon S. Cell Chemical Biology, Vol. 25, Issue 12 https://doi.org/10.1016/j.chembiol.2018.11.001	journal	December 2018
A Single Legionella Effector Catalyzes a Multistep Ubiquitination Pathway to Rearrange Tubular Endoplasmic Reticulum for Replication Kotewicz, Kristin M.; Ramabhadran, Vinay; Sjoblom, Nicole Cell Host & Microbe, Vol. 21, Issue 2 https://doi.org/10.1016/j.chom.2016.12.007	journal	February 2017
A Legionella effector ADP-ribosyltransferase inactivates glutamate dehydrogenase Black, Miles H.; Osinski, Adam; Park, Gina J. Journal of Biological Chemistry, Vol. 296 https://doi.org/10.1016/j.jbc.2021.100301	journal	January 2021
The unity of opposites: Strategic interplay between bacterial effectors to regulate cellular homeostasis Iyer, Shalini; Das, Chittaranjan Journal of Biological Chemistry, Vol. 297, Issue 6 https://doi.org/10.1016/j.jbc.2021.101340	journal	December 2021
Substrate-Assisted Catalysis by PARP10 Limits Its Activity to Mono-ADP-Ribosylation Kleine, Henning; Poreba, Elzbieta; Lesniewicz, Krzysztof Molecular Cell, Vol. 32, Issue 1 https://doi.org/10.1016/j.molcel.2008.08.009	journal	October 2008
The Toxin-Antitoxin System DarTG Catalyzes Reversible ADP-Ribosylation of DNA Jankevicius, Gytis; Ariza, Antonio; Ahel, Marijan Molecular Cell, Vol. 64, Issue 6 https://doi.org/10.1016/j.molcel.2016.11.014	journal	December 2016
Regulation of Phosphoribosyl-Linked Serine Ubiquitination by Deubiquitinases DupA and DupB Shin, Donghyuk; Mukherjee, Rukmini; Liu, Yaobin Molecular Cell, Vol. 77, Issue 1 https://doi.org/10.1016/j.molcel.2019.10.019	journal	January 2020
Threonine ADP-Ribosylation of Ubiquitin by a Bacterial Effector Family Blocks Host Ubiquitination Yan, Fujie; Huang, Chunfeng; Wang, Xiaofei Molecular Cell, Vol. 78, Issue 4 https://doi.org/10.1016/j.molcel.2020.03.016	journal	May 2020
Structural and mechanistic basis for protein glutamylation by the kinase fold Osinski, Adam; Black, Miles H.; Pawłowski, Krzysztof Molecular Cell, Vol. 81, Issue 21 https://doi.org/10.1016/j.molcel.2021.08.007	journal	November 2021
Mimetics of ADP-Ribosylated Histidine through Copper(I)-Catalyzed Click Chemistry Minnee, Hugo; Rack, Johannes G. M.; van der Marel, Gijsbert A. Organic Letters, Vol. 24, Issue 21 https://doi.org/10.1021/acs.orglett.2c01300	journal	May 2022
Synthetic α- and β-Ser-ADP-ribosylated Peptides Reveal α-Ser-ADPr as the Native Epimer Voorneveld, Jim; Rack, Johannes G. M.; Ahel, Ivan Organic Letters, Vol. 20, Issue 13 https://doi.org/10.1021/acs.orglett.8b01742	journal	June 2018
On Terminal Alkynes That Can React with Active-Site Cysteine Nucleophiles in Proteases Ekkebus, Reggy; van Kasteren, Sander I.; Kulathu, Yogesh Journal of the American Chemical Society, Vol. 135, Issue 8 https://doi.org/10.1021/ja309802n	journal	February 2013
Arginine ADP-Ribosylation: Chemical Synthesis of Post-Translationally Modified Ubiquitin Proteins Voorneveld, Jim; Kloet, Max S.; Wijngaarden, Sven Journal of the American Chemical Society, Vol. 144, Issue 45 https://doi.org/10.1021/jacs.2c06249	journal	November 2022
Deficiency of terminal ADP-ribose protein glycohydrolase TARG1/C6orf130 in neurodegenerative disease Sharifi, Reza; Morra, Rosa; Denise Appel, C. The EMBO Journal, Vol. 32, Issue 9 https://doi.org/10.1038/emboj.2013.51	journal	March 2013
The structure and catalytic mechanism of a poly(ADP-ribose) glycohydrolase Slade, Dea; Dunstan, Mark S.; Barkauskaite, Eva Nature, Vol. 477, Issue 7366 https://doi.org/10.1038/nature10404	journal	September 2011
Mechanism of phospho-ubiquitin-induced PARKIN activation Wauer, Tobias; Simicek, Michal; Schubert, Alexander Nature, Vol. 524, Issue 7565 https://doi.org/10.1038/nature14879	journal	July 2015
Ubiquitination independent of E1 and E2 enzymes by bacterial effectors Qiu, Jiazhang; Sheedlo, Michael J.; Yu, Kaiwen Nature, Vol. 533, Issue 7601 https://doi.org/10.1038/nature17657	journal	April 2016
Genomic analysis of 38 Legionella species identifies large and diverse effector repertoires Burstein, David; Amaro, Francisco; Zusman, Tal Nature Genetics, Vol. 48, Issue 2 https://doi.org/10.1038/ng.3481	journal	January 2016
Ab initio electron density determination directly from solution scattering data Grant, Thomas D. Nature Methods, Vol. 15, Issue 3 https://doi.org/10.1038/nmeth.4581	journal	January 2018
The role of ubiquitylation in immune defence and pathogen evasion Jiang, Xiaomo; Chen, Zhijian J. Nature Reviews Immunology, Vol. 12, Issue 1 https://doi.org/10.1038/nri3111	journal	December 2011
Legionella and Coxiella effectors: strength in diversity and activity Qiu, Jiazhang; Luo, Zhao-Qing Nature Reviews Microbiology, Vol. 15, Issue 10 https://doi.org/10.1038/nrmicro.2017.67	journal	July 2017
Structure of mammalian poly(ADP-ribose) glycohydrolase reveals a flexible tyrosine clasp as a substrate-binding element Kim, In-Kwon; Kiefer, James R.; Ho, Chris M. W. Nature Structural & Molecular Biology, Vol. 19, Issue 6 https://doi.org/10.1038/nsmb.2305	journal	May 2012
A family of macrodomain proteins reverses cellular mono-ADP-ribosylation Jankevicius, Gytis; Hassler, Markus; Golia, Barbara Nature Structural & Molecular Biology, Vol. 20, Issue 4 https://doi.org/10.1038/nsmb.2523	journal	March 2013
Insights into catalysis and function of phosphoribosyl-linked serine ubiquitination Kalayil, Sissy; Bhogaraju, Sagar; Bonn, Florian Nature, Vol. 557, Issue 7707 https://doi.org/10.1038/s41586-018-0145-8	journal	May 2018
Structural basis of ubiquitin modification by the Legionella effector SdeA Dong, Yanan; Mu, Yajuan; Xie, Yongchao Nature, Vol. 557, Issue 7707 https://doi.org/10.1038/s41586-018-0146-7	journal	May 2018
Mechanism of phosphoribosyl-ubiquitination mediated by a single Legionella effector Akturk, Anil; Wasilko, David J.; Wu, Xiaochun Nature, Vol. 557, Issue 7707 https://doi.org/10.1038/s41586-018-0147-6	journal	May 2018
Regulation of phosphoribosyl ubiquitination by a calmodulin-dependent glutamylase Gan, Ninghai; Zhen, Xiangkai; Liu, Yao Nature, Vol. 572, Issue 7769 https://doi.org/10.1038/s41586-019-1439-1	journal	July 2019
Inhibition of bacterial ubiquitin ligases by SidJ–calmodulin catalysed glutamylation Bhogaraju, Sagar; Bonn, Florian; Mukherjee, Rukmini Nature, Vol. 572, Issue 7769 https://doi.org/10.1038/s41586-019-1440-8	journal	July 2019
Highly accurate protein structure prediction with AlphaFold Jumper, John; Evans, Richard; Pritzel, Alexander Nature https://doi.org/10.1038/s41586-021-03819-2	journal	July 2021
Molecular basis for DarT ADP-ribosylation of a DNA base Schuller, Marion; Butler, Rachel E.; Ariza, Antonio Nature, Vol. 596, Issue 7873 https://doi.org/10.1038/s41586-021-03825-4	journal	August 2021
Inactivation of the ubiquitin conjugating enzyme UBE2Q2 causes a prophase arrest and enhanced apoptosis in response to microtubule inhibiting agents Banerjee, S.; Brooks, W. S.; Crawford, D. F. Oncogene, Vol. 26, Issue 45 https://doi.org/10.1038/sj.onc.1210471	journal	April 2007
Ubiquitin-binding domains Hurley, James H.; Lee, Sangho; Prag, Gali Biochemical Journal, Vol. 399, Issue 3 https://doi.org/10.1042/BJ20061138	journal	October 2006
Processing of protein ADP-ribosylation by Nudix hydrolases Palazzo, Luca; Thomas, Benjamin; Jemth, Ann-Sofie Biochemical Journal, Vol. 468, Issue 2 https://doi.org/10.1042/BJ20141554	journal	May 2015
Multiple substrates of the Legionella pneumophila Dot/Icm system identified by interbacterial protein transfer Luo, Z. -Q.; Isberg, R. R. Proceedings of the National Academy of Sciences, Vol. 101, Issue 3 https://doi.org/10.1073/pnas.0304916101	journal	January 2004
The Legionella effector SidC defines a unique family of ubiquitin ligases important for bacterial phagosomal remodeling Hsu, F.; Luo, X.; Qiu, J. Proceedings of the National Academy of Sciences, Vol. 111, Issue 29 https://doi.org/10.1073/pnas.1402605111	journal	July 2014
Deubiquitination of phosphoribosyl-ubiquitin conjugates by phosphodiesterase-domain–containing Legionella effectors Wan, Min; Sulpizio, Alan G.; Akturk, Anil Proceedings of the National Academy of Sciences, Vol. 116, Issue 47 https://doi.org/10.1073/pnas.1916287116	journal	November 2019
Reversible modification of mitochondrial ADP/ATP translocases by paired Legionella effector proteins Kubori, Tomoko; Lee, Junyup; Kim, Hyunmin Proceedings of the National Academy of Sciences, Vol. 119, Issue 23 https://doi.org/10.1073/pnas.2122872119	journal	June 2022
Reversibility of arginine-specific mono(ADP-ribosyl)ation: identification in erythrocytes of an ADP-ribose-L-arginine cleavage enzyme. Moss, J.; Jacobson, M. K.; Stanley, S. J. Proceedings of the National Academy of Sciences, Vol. 82, Issue 17 https://doi.org/10.1073/pnas.82.17.5603	journal	September 1985
TopDraw: a sketchpad for protein structure topology cartoons Bond, C. S. Bioinformatics, Vol. 19, Issue 2 https://doi.org/10.1093/bioinformatics/19.2.311	journal	January 2003
Automatic generation of protein structure cartoons with Pro-origami Stivala, A.; Wybrow, M.; Wirth, A. Bioinformatics, Vol. 27, Issue 23 https://doi.org/10.1093/bioinformatics/btr575	journal	October 2011
Pfam: The protein families database in 2021 Mistry, Jaina; Chuguransky, Sara; Williams, Lowri Nucleic Acids Research, Vol. 49, Issue D1 https://doi.org/10.1093/nar/gkaa913	journal	October 2020
AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models Varadi, Mihaly; Anyango, Stephen; Deshpande, Mandar Nucleic Acids Research, Vol. 50, Issue D1 https://doi.org/10.1093/nar/gkab1061	journal	November 2021
TARG1 protects against toxic DNA ADP-ribosylation Tromans-Coia, Callum; Sanchi, Andrea; Moeller, Giuliana K. Nucleic Acids Research, Vol. 49, Issue 18 https://doi.org/10.1093/nar/gkab771	journal	September 2021
HMMER web server: interactive sequence similarity searching Finn, R. D.; Clements, J.; Eddy, S. R. Nucleic Acids Research, Vol. 39, Issue suppl https://doi.org/10.1093/nar/gkr367	journal	May 2011
Depth: a web server to compute depth, cavity sizes, detect potential small-molecule ligand-binding cavities and predict the pKa of ionizable residues in proteins Tan, Kuan Pern; Nguyen, Thanh Binh; Patel, Siddharth Nucleic Acids Research, Vol. 41, Issue W1 https://doi.org/10.1093/nar/gkt503	journal	June 2013
(ADP-ribosyl)hydrolases: structure, function, and biology Rack, Johannes Gregor Matthias; Palazzo, Luca; Ahel, Ivan Genes & Development, Vol. 34, Issue 5-6 https://doi.org/10.1101/gad.334631.119	journal	February 2020
BioXTAS RAW : improvements to a free open-source program for small-angle X-ray scattering data reduction and analysis Hopkins, Jesse Bennett; Gillilan, Richard E.; Skou, Soren Journal of Applied Crystallography, Vol. 50, Issue 5 https://doi.org/10.1107/S1600576717011438	journal	September 2017
Improved radiation dose efficiency in solution SAXS using a sheath flow sample environment Kirby, Nigel; Cowieson, Nathan; Hawley, Adrian M. Acta Crystallographica Section D Structural Biology, Vol. 72, Issue 12 https://doi.org/10.1107/S2059798316017174	journal	November 2016
Bacterial pseudokinase catalyzes protein polyglutamylation to inhibit the SidE-family ubiquitin ligases Black, Miles H.; Osinski, Adam; Gradowski, Marcin Science, Vol. 364, Issue 6442 https://doi.org/10.1126/science.aaw7446	journal	May 2019
Toxicity and SidJ-Mediated Suppression of Toxicity Require Distinct Regions in the SidE Family of Legionella pneumophila Effectors Havey, James C.; Roy, Craig R. Infection and Immunity, Vol. 83, Issue 9 https://doi.org/10.1128/IAI.00497-15	journal	June 2015
ADP-Ribosylation of Rab5 by ExoS of Pseudomonas aeruginosa Affects Endocytosis Barbieri, Alejandro M.; Sha, Qun; Bette-Bobillo, Pascale Infection and Immunity, Vol. 69, Issue 9 https://doi.org/10.1128/IAI.69.9.5329-5334.2001	journal	September 2001
The Legionella Effector SdjA Is a Bifunctional Enzyme That Distinctly Regulates Phosphoribosyl Ubiquitination Song, Lei; Xie, Yongchao; Li, Chuang mBio, Vol. 12, Issue 5 https://doi.org/10.1128/mBio.02316-21	journal	October 2021
Macrodomains: Structure, Function, Evolution, and Catalytic Activities Rack, Johannes Gregor Matthias; Perina, Dragutin; Ahel, Ivan Annual Review of Biochemistry, Vol. 85, Issue 1 https://doi.org/10.1146/annurev-biochem-060815-014935	journal	June 2016
Skylign: a tool for creating informative, interactive logos representing sequence alignments and profile hidden Markov models Wheeler, Travis J.; Clements, Jody; Finn, Robert D. BMC Bioinformatics, Vol. 15, Issue 1 https://doi.org/10.1186/1471-2105-15-7	journal	January 2014
Fully Flexible Docking of Medium Sized Ligand Libraries with RosettaLigand DeLuca, Samuel; Khar, Karen; Meiler, Jens PLOS ONE, Vol. 10, Issue 7 https://doi.org/10.1371/journal.pone.0132508	journal	July 2015
Legionella Metaeffector Exploits Host Proteasome to Temporally Regulate Cognate Effector Kubori, Tomoko; Shinzawa, Naoaki; Kanuka, Hirotaka PLoS Pathogens, Vol. 6, Issue 12 https://doi.org/10.1371/journal.ppat.1001216	journal	December 2010
Diverse mechanisms of metaeffector activity in an intracellular bacterial pathogen, Legionella pneumophila Urbanus, Malene L.; Quaile, Andrew T.; Stogios, Peter J. Molecular Systems Biology, Vol. 12, Issue 12 https://doi.org/10.15252/msb.20167381	journal	December 2016
Exploitation of the Host Ubiquitin System: Means by Legionella pneumophila Luo, Jingjing; Wang, Lidong; Song, Lei Frontiers in Microbiology, Vol. 12 https://doi.org/10.3389/fmicb.2021.790442	journal	December 2021
Structural and Functional Characterization of Legionella pneumophila Effector MavL Voth, Kevin; Pasricha, Shivani; Chung, Ivy Yeuk Wah Biomolecules, Vol. 11, Issue 12 https://doi.org/10.3390/biom11121802	journal	November 2021
Protein polyglutamylation catalyzed by the bacterial calmodulin-dependent pseudokinase SidJ Sulpizio, Alan; Minelli, Marena E.; Wan, Min eLife, Vol. 8 https://doi.org/10.7554/eLife.51162	journal	November 2019
Interplay between bacterial deubiquitinase and ubiquitin E3 ligase regulates ubiquitin dynamics on Legionella phagosomes Liu, Shuxin; Luo, Jiwei; Zhen, Xiangkai eLife, Vol. 9 https://doi.org/10.7554/eLife.58114	journal	November 2020
Bacterial OTU deubiquitinases regulate substrate ubiquitination upon Legionella infection Shin, Donghyuk; Bhattacharya, Anshu; Cheng, Yi-Lin eLife, Vol. 9 https://doi.org/10.7554/eLife.58277	journal	November 2020
Legionella pneumophila modulates host energy metabolism by ADP-ribosylation of ADP/ATP translocases Fu, Jiaqi; Zhou, Mowei; Gritsenko, Marina A. eLife, Vol. 11 https://doi.org/10.7554/eLife.73611	journal	January 2022

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