Electronic versions

DOI

  • Andrew T Quaile
    University of Toronto
  • Peter J Stogios
    University of Toronto
  • Olga Egorova
    University of Toronto
  • Elena Evdokimova
    University of Toronto
  • Dylan Valleau
    University of Toronto
  • Boguslaw Nocek
    Midwest Center for Structural Genomics and Structural Biology Center
  • Purnima S Kompella
    University of Toronto
  • Sergio Peisajovich
    University of Toronto
  • Alexander F Yakunin
    University of Toronto
  • Alexander W Ensminger
    University of Toronto
  • Alexei Savchenko
    University of Toronto

Host colonization by Gram-negative pathogens often involves delivery of bacterial proteins called "effectors" into the host cell. The pneumonia-causing pathogen Legionella pneumophila delivers more than 330 effectors into the host cell via its type IVB Dot/Icm secretion system. The collective functions of these proteins are the establishment of a replicative niche from which Legionella can recruit cellular materials to grow while evading lysosomal fusion inhibiting its growth. Using a combination of structural, biochemical, and in vivo approaches, we show that one of these translocated effector proteins, Ceg4, is a phosphotyrosine phosphatase harboring a haloacid dehalogenase-hydrolase domain. Ceg4 could dephosphorylate a broad range of phosphotyrosine-containing peptides in vitro and attenuated activation of MAPK-controlled pathways in both yeast and human cells. Our findings indicate that L. pneumophila's infectious program includes manipulation of phosphorylation cascades in key host pathways. The structural and functional features of the Ceg4 effector unraveled here provide first insight into its function as a phosphotyrosine phosphatase, paving the way to further studies into L. pneumophila pathogenicity.

Keywords

  • Endoplasmic Reticulum/metabolism, Enzyme Activation, HeLa Cells, Host-Pathogen Interactions, Humans, Legionella pneumophila/enzymology, MAP Kinase Signaling System, Mitogen-Activated Protein Kinases/metabolism, Phosphorylation, Protein Transport, Protein Tyrosine Phosphatases/metabolism, Saccharomyces cerevisiae Proteins/metabolism, p38 Mitogen-Activated Protein Kinases/metabolism
Original languageEnglish
Pages (from-to)3307-3320
Number of pages14
JournalJournal of Biological Chemistry
Volume293
Issue number9
Early online date4 Jan 2018
DOIs
Publication statusPublished - 2 Mar 2018
Externally publishedYes
View graph of relations