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Regulation of phosphoribosyl ubiquitination by a calmodulin-dependent glutamylase.

<div class='caption-title'>a. SidJ suppresses the yeast toxicity of SdeAH277A. Diluted cells from yeast strains inducible expressing SdeA or SdeAH277A that harbor the vector or a SidJ construct were spotted onto the indicated media and grew for 2 d (top). The expression of relevant proteins was probed by immunoblotting (bottom). The 3-phosphoglyceric phosphokinase-1 (PGK1) was probed as a loading control. V, vector.</div>
<div class='caption-title'>a. Flag-SdeA coexpressed with SidJ fails to modify Rab33b. Flag-SdeA from HEK293T cells coexpressing relevant proteins was used to ubiquitinate 4xFlag-Rab33b. Ub-Rab33b was detected as described in Fig. 1. SidJDD/AA is a SidJ mutant defective in suppressing the yeast toxicity of SdeA that carries D542A and D545A mutations.</div>
<div class='caption-title'>a. SidJ harbors an IQ motif. Alignment of the IQ domain of SidJ and that of several CaM-binding proteins. Conserved residues were highlighted in red. The accession number for each protein was included.</div>
Gan N, Zhen X, Liu Y, Xu X, He C, Qiu J, Liu Y, Fujimoto GM, Nakayasu ES, Zhou B, Zhao L, Puvar K, Das C, Ouyang S, Luo ZQ
OpenAccess logo Nature 572 387-391 (2019)
Related entries: 6k4k, 6k4l

Cited: 56 times
EuropePMC logo PMID: 31330531

Abstract

The bacterial pathogen Legionella pneumophila creates an intracellular niche permissive for its replication by extensively modulating host-cell functions using hundreds of effector proteins delivered by its Dot/Icm secretion system1. Among these, members of the SidE family (SidEs) regulate several cellular processes through a unique phosphoribosyl ubiquitination mechanism that bypasses the canonical ubiquitination machinery2-4. The activity of SidEs is regulated by another Dot/Icm effector known as SidJ5; however, the mechanism of this regulation is not completely understood6,7. Here we demonstrate that SidJ inhibits the activity of SidEs by inducing the covalent attachment of glutamate moieties to SdeA-a member of the SidE family-at E860, one of the catalytic residues that is required for the mono-ADP-ribosyltransferase activity involved in ubiquitin activation2. This inhibition by SidJ is spatially restricted in host cells because its activity requires the eukaryote-specific protein calmodulin (CaM). We solved a structure of SidJ-CaM in complex with AMP and found that the ATP used in this reaction is cleaved at the α-phosphate position by SidJ, which-in the absence of glutamate or modifiable SdeA-undergoes self-AMPylation. Our results reveal a mechanism of regulation in bacterial pathogenicity in which a glutamylation reaction that inhibits the activity of virulence factors is activated by host-factor-dependent acyl-adenylation.

Reviews - 6k4r mentioned but not cited (2)

  1. Catalytic activity regulation through post-translational modification: the expanding universe of protein diversity. Kokkinidis M, Glykos NM, Fadouloglou VE. Adv Protein Chem Struct Biol 122 97-125 (2020)
  2. The unity of opposites: Strategic interplay between bacterial effectors to regulate cellular homeostasis. Iyer S, Das C. J Biol Chem 297 101340 (2021)

Articles - 6k4r mentioned but not cited (1)



Reviews citing this publication (17)

  1. Tutorial: best practices and considerations for mass-spectrometry-based protein biomarker discovery and validation. Nakayasu ES, Gritsenko M, Piehowski PD, Gao Y, Orton DJ, Schepmoes AA, Fillmore TL, Frohnert BI, Rewers M, Krischer JP, Ansong C, Suchy-Dicey AM, Evans-Molina C, Qian WJ, Webb-Robertson BM, Metz TO. Nat Protoc 16 3737-3760 (2021)
  2. An expanded lexicon for the ubiquitin code. Dikic I, Schulman BA. Nat Rev Mol Cell Biol 24 273-287 (2023)
  3. ADP-ribosylation systems in bacteria and viruses. Mikolčević P, Hloušek-Kasun A, Ahel I, Mikoč A. Comput Struct Biotechnol J 19 2366-2383 (2021)
  4. Molecular Mimicry: a Paradigm of Host-Microbe Coevolution Illustrated by Legionella. Mondino S, Schmidt S, Buchrieser C. mBio 11 e01201-20 (2020)
  5. Divergence of Legionella Effectors Reversing Conventional and Unconventional Ubiquitination. Kitao T, Nagai H, Kubori T. Front Cell Infect Microbiol 10 448 (2020)
  6. Regulation of cGAS-Mediated Immune Responses and Immunotherapy. Saeed AFUH, Ruan X, Guan H, Su J, Ouyang S. Adv Sci (Weinh) 7 1902599 (2020)
  7. Exploitation of the Host Ubiquitin System: Means by Legionella pneumophila. Luo J, Wang L, Song L, Luo ZQ. Front Microbiol 12 790442 (2021)
  8. Evolution and Adaptation of Legionella pneumophila to Manipulate the Ubiquitination Machinery of Its Amoebae and Mammalian Hosts. Price CTD, Abu Kwaik Y. Biomolecules 11 112 (2021)
  9. Affecting the Effectors: Regulation of Legionella pneumophila Effector Function by Metaeffectors. Joseph AM, Shames SR. Pathogens 10 108 (2021)
  10. Ubiquitin-targeted bacterial effectors: rule breakers of the ubiquitin system. Roberts CG, Franklin TG, Pruneda JN. EMBO J 42 e114318 (2023)
  11. "Make way": Pathogen exploitation of membrane traffic. Noack J, Mukherjee S. Curr Opin Cell Biol 65 78-85 (2020)
  12. Polyglutamylation: biology and analysis. Ruse CI, Chin HG, Pradhan S. Amino Acids 54 529-542 (2022)
  13. The ubiquitin codes in cellular stress responses. Sheng X, Xia Z, Yang H, Hu R. Protein Cell 15 157-190 (2024)
  14. Ubiquitin-regulating effector proteins from Legionella. Jeong M, Jeon H, Shin D. BMB Rep 55 316-322 (2022)
  15. Deciphering non-canonical ubiquitin signaling: biology and methodology. van Overbeek NK, Aguirre T, van der Heden van Noort GJ, Blagoev B, Vertegaal ACO. Front Mol Biosci 10 1332872 (2023)
  16. Legionella pneumophila-mediated host posttranslational modifications. Yang Y, Mei L, Chen J, Chen X, Wang Z, Liu L, Yang A. J Mol Cell Biol 15 mjad032 (2023)
  17. Mechanism and Modulation of SidE Family Proteins in the Pathogenesis of Legionella pneumophila. Xie Y, Zhang Y, Wang Y, Feng Y. Pathogens 12 629 (2023)

Articles citing this publication (36)



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