Salmonella AvrA Coordinates Suppression of Host Immune and Apoptotic Defenses via JNK Pathway Blockade

Abstract

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.

The Arabidopsis ZED1 pseudokinase is required for ZAR1-mediated immunity induced by the Pseudomonas syringae type III effector HopZ1a

“…HopZ1a may have originally evolved to acetylate an immunerelated kinase to suppress plant immunity similar to the function of other members of the YopJ superfamily (11,12,30,39,40). We speculate that HopZ1a-induced virulence involves manipulation of a ZED1-related kinase, in addition to other known virulence targets like microtubules (18).…”

Impact ofSalmonella entericaType III Secretion System Effectors on the Eukaryotic Host Cell

“…These studies suggested that AvrA inhibits the NF-κB pathway [175]. Inhibition of c-Jun N-terminal kinase (JNK) and NF-κB signaling pathways were observed in transgenic Drosophila and murine models leading to suppression of innate immunity, inflammation, and apoptosis during natural infection [176]. Recently, DNA microarray analysis of mouse colon mucosa infected with wild-type or AvrA − Salmonella suggested that several pathways, including mTOR, NF-κB, platelet-derived growth factors, vascular endothelial growth factor, oxidative phosphorylation, and MAPK signaling, are specifically regulated by AvrA in vivo [127].…”

“…This, in turn, stabilizes β-catenin, a downstream target of Wnt. Proposed targets for the acetyltransferase activity of AvrA are MAPK kinase 4 (MKK4) in a Drosophila model, leading to inhibition of JNK [176] and p53. p53 acetylation is increased by AvrA in vitro and in an in vivo mouse model.…”

Salmonella: Invasion, Evasion & Persistence

“…SptP GAP and tyrosine phosphatase activities play critical roles in reversing MAPK activation while AvrA acetyltransferase activity towards MAPK kinases inhibits Jnk activation (Jones et al, 2008;Lin et al, 2003;Murli et al, 2001). Moreover, SpvC has been shown to directly inhibit Erk, Jnk and p38 MAPKs via its phosphothreonine lyase activity (Li et al, 2007;Mazurkiewicz et al, 2008).…”