The Legionella pneumophila effector Ceg4 is a phosphotyrosine phosphatase that attenuates activation of eukaryotic MAPK pathways
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In: Journal of Biological Chemistry, Vol. 293, No. 9, 02.03.2018, p. 3307-3320.
Research output: Contribution to journal › Article › peer-review
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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 -