Author(s): Yong-guo Zhang 1 , Shaoping Wu 1 , Yinglin Xia 2 , Di Chen 1 , Elaine O. Petrof 3 , Erika C. Claud 4 , Wei Hsu 5 , Jun Sun 1 , 6 , *
Axin1 and 2 belong to the Axin family, a negative regulator of the Wnt signaling pathway and a key player in developmental processes and pathogenesis of human diseases , , , . Axin forms a complex with GSK-3[beta] an [beta]-catenin and promotes GSK-3[beta]-dependent phosphorylation of [beta]-catenin , , . In normal cells, [beta]-catenin levels are kept low through interactions with GSK-3[beta], APC, and Axin , , , . Dishevelled (Dsh) is the upstream regulator of the [beta]-catenin pathway. At the C-terminal end, Axin can bind with Dsh and this interaction reduces [beta]-catenin binding , , , . Recently, more evidence demonstrates that Axin is involved in many other signaling pathways, including mTOR14, JNK MAPK15, parathyroid hormone16, and p53 signaling , , .
Bacterial infection is a stress to the host. Pathogens use a type three secretion system (TTSS) to inject bacterial pathogenic proteins, called effectors, into host cells . Virulence bacterial effectors, such as Salmonell a AvrA, mimic the activity of a eukaryotic protein and debilitate their target cells . Our publications and those of others demonstrate that [beta]-catenin/Wnt , , , , , , , JNK/MAPK , , and p53  are involved in bacterial infection and intestinal inflammation. Axin is a key player for the [beta]-catenin/Wnt, JNK and p53 pathways. However, it is not known whether Axin directly regulates Salmonella -induced inflammation in the intestine.
In this current study, we investigated the molecular mechanism and physiological roles of Axin1-Salmonella interactions. We found that pathogenic Salmonella colonization decreased the Axin1 protein expression in intestinal epithelial cells at the post-transcriptional level. Bacterial protein AvrA expression stabilizes Axin1 protein and beta-catenin/Axin interactions. Axin1 exhibited a specific role in inhibiting Salmonella invasion and bacterial inflammation. It is affected by the level of Axin1, but not Axin2. The resulting data indicate an essential role of intestinal Axin1 in modulating host defense against pathogen-induced inflammation.
Axin1 responds to Salmonella treatment
To determine whether Axin protein plays a role in epithelial- Salmonella interactions, we tested human intestinal epithelial HCT116 cells with wild-type (WT) Salmonella ATCC 14028s. We found that WT Salmonella significantly decreased the total amount of Axin1 in host cells after bacterial colonization for only 1 hour (Fig. 1A. HCT116). To look at the generality of our observation, we further investigated the response in the human colonic epithelial cell lines HT29C19A and CaCo2BBE. We had to use these cell lines because there is no non-cancer and non-transformed colon cell line available in the field. A similar change in Axin1 reduction by pathogenic WT Salmonella was found (Fig. 1A). To test if the response is specific to Salmonella , we also treated cells with inflammatory cytokine TNF-a, human commensal bacterial E. coli F18, and probiotic strain Lactobacillus rhamnosus GG (Fig. 1B). However, we did not...