Salmonella AvrA Coordinates Suppression of Host Immune and Apoptotic Defenses via JNK Pathway Blockade.
Salmonellae are bacterial pathogens that have evolved sophisticated strategies to evade host immune defenses. These strategies include the secretion of effector proteins into mammalian cells so as to subvert innate immune and apoptotic signaling pathways, thereby allowing Salmonella to avoid elimination. Here, we show that the secreted Salmonella typhimurium effector protein AvrA possesses acetyltransferase activity toward specific mitogen-activated protein kinase kinases (MAPKKs) and potently inhibits c-Jun N-terminal kinase (JNK) and NF-kappaB signaling pathways in both transgenic Drosophila and murine models. Furthermore, we show that AvrA dampens the proapoptotic innate immune response to Salmonella at the mouse intestinal mucosa. This activity is consistent with the natural history of Salmonella in mammalian hosts, where the bacteria elicit transient inflammation but do not destroy epithelial cells. Our findings suggest that targeting JNK signaling to dampen apoptosis may be a conserved strategy for intracellular pathogens.
Jones
Rheinallt M
RM
Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Wu
Huixia
H
Wentworth
Christy
C
Luo
Liping
L
Collier-Hyams
Lauren
L
Neish
Andrew S
AS
D000123:Acetyltransferases / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000502:physiology*; D001426:Bacterial Proteins / Q000378:metabolism*; D015536:Down-Regulation; D004330:Drosophila; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D007413:Intestinal Mucosa / Q000276:immunology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D012480:Salmonella Infections / Q000276:immunology* / Q000378:metabolism*; D012486:Salmonella typhimurium / Q000201:enzymology*; D015398:Signal Transduction
C487891:AvrA protein, Salmonella typhimurium; D001426:Bacterial Proteins; D016328:NF-kappa B; D000123:Acetyltransferases; D048031:JNK Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases