title: The Salmonella kinase SteC targets the MAP kinase MEK to regulate the host actin cytoskeleton.
abstract: After host cell entry, Salmonella replicate in membrane-bound compartments, which accumulate a dense meshwork of F-actin through the kinase activity of the Salmonella SPI-2 type III secretion effector SteC. We find that SteC promotes actin cytoskeleton reorganization by activating a signaling pathway involving the MAP kinases MEK and ERK, myosin light chain kinase (MLCK) and Myosin IIB. Specifically, SteC phosphorylates MEK directly on serine 200 (S200), a previously unstudied phosphorylation site. S200 phosphorylation is predicted to displace a negative regulatory helix causing autophosphorylation on the known MEK activatory residues, S218 and S222. In support of this, substitution of S200 with alanine prevented phosphorylation on S218 and S222, and phosphomimetic mutations of S200 stimulated phosphorylation of these residues. Both steC-null and kinase-deficient mutant strains displayed enhanced replication in infected cells, suggesting that SteC manipulates the actin cytoskeleton to restrain bacterial growth, thereby regulating virulence.
authors.affiliation: Section of Microbiology, MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London SW7 2AZ, UK.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Odendall
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rolhion
authors.forename: Andreas
authors.initials: A
authors.lastname: Förster
authors.forename: John
authors.initials: J
authors.lastname: Poh
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Lamont
authors.forename: Mei
authors.initials: M
authors.lastname: Liu
authors.forename: Paul S
authors.initials: PS
authors.lastname: Freemont
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Catling
authors.forename: David W
authors.initials: DW
authors.lastname: Holden
mesh_terms: D016475:3T3 Cells; D008841:Actin Cytoskeleton / Q000378:metabolism*; D019943:Amino Acid Substitution; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism; D024501:Nonmuscle Myosin Type IIB / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D012481:Salmonella Infections, Animal / Q000382:microbiology; D012486:Salmonella typhimurium / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*
chemical_list: D011494:Protein Kinases; C526376:SteC protein, Salmonella typhimurium; D009219:Myosin-Light-Chain Kinase; D020929:Mitogen-Activated Protein Kinase Kinases; D024501:Nonmuscle Myosin Type IIB