Modulation of host apoptotic signaling by the Salmonella effector protein AvrA

Abstract

Certain enteric pathogens stably establish themselves within host cells because they have evolved mechanisms to evade elimination. For example, the intracellular pathogen Salmonella secretes the AvrA protein which has potent suppressive effects on innate immune and apoptotic pathways. To determine the mechanism by which AvrA mediates these effects, we created transgenic Drosophila harboring avrA, allowing directed expression of AvrA in Drosophila tissues. We show that AvrA has potent and specific inhibitory activity against the JNK pathway in Drosophila and in cultured mammalian cells. Intriguingly, we also found that AvrA expression in a background of constitutive JNK pathway activation resulted in increased proliferation of Drosophila tissue whereas AvrA expression in a wild type background did not. Furthermore, reporter gene assays in cultured cells showed AvrA mediated inhibition of constitutive JNK pathway activation resulted in increased ERK signaling. We also show that the mechanism by which AvrA mediates JNK pathway inhibition is via the acetylation of the activation loop threonine of MKK4 ‐ a residue necessarily phosphorylated during activation of this enzyme. Together, these studies show Salmonella has evolved a protein that inhibits the pro‐apoptotic JNK pathway, with the secondary effect of dysregulating normal tissue growth. Research funding provided by Burroughs Welcome Fund.