The Shigella flexneri effector OspG interferes with innate immune responses by targeting ubiquitin-conjugating enzymes.
Bacteria of Shigella spp. are responsible for shigellosis in humans. They use a type III secretion system to inject effector proteins into host cells and induce their entry into epithelial cells or trigger apoptosis in macrophages. We present evidence that the effector OspG is a protein kinase that binds various ubiquitinylated ubiquitin-conjugating enzymes, including UbcH5, which belongs to the stem cell factor SCF(beta-TrCP) complex promoting ubiquitination of phosphorylated inhibitor of NF-kappaB type alpha (phospho-IkappaBalpha). Transfection experiments indicated that OspG can prevent phospho-IkappaBalpha degradation and NF-kappaB activation induced by TNF-alpha stimulation. Infection of epithelial cells by the S. flexneri wild-type strain, but not an ospG mutant, led to accumulation of phospho-IkappaBalpha, consistent with OspG inhibiting SCF(beta-TrCP) activity. Upon infection of ileal loops in rabbits, the ospG mutant induced a stronger inflammatory response than the wild-type strain. This finding indicates that OspG negatively controls the host innate response induced by S. flexneri upon invasion of the epithelium.
Kim
Dong Wook
DW
Unité de Pathogénie Microbienne Moléculaire, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 389, Institut Pasteur, 28 Rue du Dr. Roux, 75015 Paris, France.
Lenzen
Gerlinde
G
Page
Anne-Laure
AL
Legrain
Pierre
P
Sansonetti
Philippe J
PJ
Parsot
Claude
C
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004405:Dysentery, Bacillary / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology*; D006801:Humans; D007082:Ileum / Q000382:microbiology / Q000473:pathology; D007113:Immunity, Innate; D007413:Intestinal Mucosa / Q000382:microbiology; D033862:Iron-Binding Proteins / Q000378:metabolism; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D011817:Rabbits; D012763:Shigella flexneri / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity*; D044763:Ubiquitin-Conjugating Enzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism
D001426:Bacterial Proteins; D033862:Iron-Binding Proteins; D016328:NF-kappa B; C097308:UBE2D1 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D011494:Protein Kinases