Structural basis for the toxicity of Legionella pneumophila effector SidH

Rahul Sharma, Michael Adams, Simonne Griffith-Jones, Tobias Sahr, Laura Gomez-Valero, Felix Weis, Michael Hons, Sarah Gharbi, Rayene Berkane, Alexandra Stolz, Carmen Buchrieser and Sagar Bhogaraju ()
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Rahul Sharma: European Molecular Biology Laboratory, 71 avenue des Martyrs
Michael Adams: European Molecular Biology Laboratory, 71 avenue des Martyrs
Simonne Griffith-Jones: European Molecular Biology Laboratory, 71 avenue des Martyrs
Tobias Sahr: Institut Pasteur, Université Paris Cité, Biologie des Bactéries Intracellulaires and CNRS UMR 6047
Laura Gomez-Valero: Institut Pasteur, Université Paris Cité, Biologie des Bactéries Intracellulaires and CNRS UMR 6047
Felix Weis: European Molecular Biology Laboratory
Michael Hons: European Molecular Biology Laboratory, 71 avenue des Martyrs
Sarah Gharbi: European Molecular Biology Laboratory, 71 avenue des Martyrs
Rayene Berkane: Institute of Biochemistry II, Goethe University Frankfurt - Medical Faculty, University Hospital
Alexandra Stolz: Institute of Biochemistry II, Goethe University Frankfurt - Medical Faculty, University Hospital
Carmen Buchrieser: Institut Pasteur, Université Paris Cité, Biologie des Bactéries Intracellulaires and CNRS UMR 6047
Sagar Bhogaraju: European Molecular Biology Laboratory, 71 avenue des Martyrs

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Legionella pneumophila (LP) secretes more than 300 effectors into the host cytosol to facilitate intracellular replication. One of these effectors, SidH, 253 kDa in size with no sequence similarity to proteins of known function is toxic when overexpressed in host cells. SidH is regulated by the LP metaeffector LubX which targets SidH for degradation in a temporal manner during LP infection. The mechanism underlying the toxicity of SidH and its role in LP infection are unknown. Here, we determined the cryo-EM structure of SidH at 2.7 Å revealing a unique alpha helical arrangement with no overall similarity to known protein structures. Surprisingly, purified SidH came bound to a E. coli EF-Tu/t-RNA/GTP ternary complex which could be modeled into the cryo-EM density. Mutation of residues disrupting the SidH-tRNA interface and SidH-EF-Tu interface abolish the toxicity of overexpressed SidH in human cells, a phenotype confirmed in infection of Acanthamoeba castellani. We also present the cryo-EM structure of SidH in complex with a U-box domain containing ubiquitin ligase LubX delineating the mechanism of regulation of SidH. Our data provide the basis for the toxicity of SidH and into its regulation by the metaeffector LubX.

Date: 2023
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DOI: 10.1038/s41467-023-42683-8

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