TY - JOUR

T1 - The Legionella pneumophila effector Ceg4 is a phosphotyrosine phosphatase that attenuates activation of eukaryotic MAPK pathways

AU - Quaile, Andrew T

AU - Stogios, Peter J

AU - Egorova, Olga

AU - Evdokimova, Elena

AU - Valleau, Dylan

AU - Nocek, Boguslaw

AU - Kompella, Purnima S

AU - Peisajovich, Sergio

AU - Yakunin, Alexander F

AU - Ensminger, Alexander W

AU - Savchenko, Alexei

PY - 2018/3/2

Y1 - 2018/3/2

N2 - 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.

AB - 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.

KW - Endoplasmic Reticulum/metabolism

KW - Enzyme Activation

KW - HeLa Cells

KW - Host-Pathogen Interactions

KW - Humans

KW - Legionella pneumophila/enzymology

KW - MAP Kinase Signaling System

KW - Mitogen-Activated Protein Kinases/metabolism

KW - Phosphorylation

KW - Protein Transport

KW - Protein Tyrosine Phosphatases/metabolism

KW - Saccharomyces cerevisiae Proteins/metabolism

KW - p38 Mitogen-Activated Protein Kinases/metabolism

U2 - 10.1074/jbc.M117.812727

DO - 10.1074/jbc.M117.812727

M3 - Article

C2 - 29301934

VL - 293

SP - 3307

EP - 3320

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 9

ER -