Inhibition of bacterial ubiquitin ligases by SidJ–calmodulin catalysed glutamylation

Sagar Bhogaraju (), Florian Bonn, Rukmini Mukherjee, Michael Adams, Moritz M. Pfleiderer, Wojciech P. Galej, Vigor Matkovic, Jaime Lopez-Mosqueda, Sissy Kalayil, Donghyuk Shin and Ivan Dikic ()
Additional contact information
Sagar Bhogaraju: Goethe University
Florian Bonn: Goethe University
Rukmini Mukherjee: Goethe University
Michael Adams: European Molecular Biology Laboratory
Moritz M. Pfleiderer: European Molecular Biology Laboratory
Wojciech P. Galej: European Molecular Biology Laboratory
Vigor Matkovic: Goethe University
Jaime Lopez-Mosqueda: Goethe University
Sissy Kalayil: Goethe University
Donghyuk Shin: Goethe University
Ivan Dikic: Goethe University

Nature, 2019, vol. 572, issue 7769, 382-386

Abstract: Abstract The family of bacterial SidE enzymes catalyses phosphoribosyl-linked serine ubiquitination and promotes infectivity of Legionella pneumophila, a pathogenic bacteria that causes Legionnaires’ disease1–3. SidE enzymes share the genetic locus with the Legionella effector SidJ that spatiotemporally opposes the toxicity of these enzymes in yeast and mammalian cells, through a mechanism that is currently unknown4–6. Deletion of SidJ leads to a substantial defect in the growth of Legionella in both its natural hosts (amoebae) and in mouse macrophages4,5. Here we demonstrate that SidJ is a glutamylase that modifies the catalytic glutamate in the mono-ADP ribosyl transferase domain of the SdeA, thus blocking the ubiquitin ligase activity of SdeA. The glutamylation activity of SidJ requires interaction with the eukaryotic-specific co-factor calmodulin, and can be regulated by intracellular changes in Ca2+ concentrations. The cryo-electron microscopy structure of SidJ in complex with human apo-calmodulin revealed the architecture of this heterodimeric glutamylase. We show that, in cells infected with L. pneumophila, SidJ mediates the glutamylation of SidE enzymes on the surface of vacuoles that contain Legionella. We used quantitative proteomics to uncover multiple host proteins as putative targets of SidJ-mediated glutamylation. Our study reveals the mechanism by which SidE ligases are inhibited by a SidJ–calmodulin glutamylase, and opens avenues for exploring an understudied protein modification (glutamylation) in eukaryotes.

Date: 2019
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DOI: 10.1038/s41586-019-1440-8

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