Salmonella effector AvrA regulation of colonic epithelial cell inflammation by deubiquitination
Salmonella effector AvrA regulation of colonic epithelial cell inflammation by deubiquitination
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DOI：
10.2353/ajpath.2007.070220
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发表时间：
2007-09-01
影响因子：
6
通讯作者：
Sun, Jun
中科院分区：
文献类型：
--
作者：
Ye, Zhongde;Petrof, Elaine O.;Sun, Jun
AvrA 是一种新描述的存在于沙门氏菌中的细菌效应子。在这里，我们测试了这样的假设：AvrA 是一种去泛素酶，可以去除核因子 kappa B (NF-kappa B) 通路的两种抑制剂（I kappa B α 和 β-连环蛋白）中的泛素，从而抑制宿主的炎症反应。在肠上皮细胞模型和感染 AvrA 缺陷和 AvrA 充足沙门氏菌菌株的小鼠模型中评估了 AvrA 的作用。我们还纯化了 AvrA 和 AvrA 突变蛋白，并在无细胞系统中表征了它们的去泛素酶活性。我们研究了靶基因和炎症细胞因子的表达，以及体内 AvrA 缺陷和充足菌株对上皮细胞增殖和凋亡的影响。我们的结果表明，AvrA 可阻止上皮细胞中 I kappa B α 和 β-连环蛋白的降解。 AvrA 使 I kappa B α 去泛素化，从而阻止其降解并导致 NF-kappa B 激活受到抑制。在表达 AvrA 的沙门氏菌感染期间，NF-kappa B 通路的靶基因（例如 IL-6）相应下调。 AvrA 还可去泛素化，从而阻止 β-连环蛋白的降解。 β-catenin 通路的靶基因，例如 c-myc 和 cyclinD1，随着 AvrA 的表达而相应上调。 β-连环蛋白的增加进一步对 NF-kappa B 通路产生负调节。我们的研究结果表明 AvrA 在通过 NF-κ B 和 β-catenin 通路调节宿主炎症反应中发挥着重要作用。
AvrA is a newly described bacterial effector existing in Salmonella. Here, we test the hypothesis that AvrA is a deubiquitinase that removes ubiquitin from two inhibitors of the nuclear factor-kappa B (NF-kappa B) pathway, I kappa B alpha and beta-catenin, thereby inhibiting the inflammatory responses of the host. The role of AvrA was assessed in intestinal epithelial cell models and in mouse models infected with AvrA-deficient and -sufficient Salmonella strains. We also purified AvrA and AvrA mutant proteins and characterized their deubiquitinase activity in a cell-free system. we investigated target gene and inflammatory cytokine expression, as well as effects on epithelial cell proliferation and apoptosis induced by AvrA-deficient and -sufficient bacterial strains in vivo. Our results show that AvrA blocks degradation of I kappa B alpha and beta-catenin in epithelial cells. AvrA deubiquitinates I kappa B alpha, which blocks its degradation and leads to the inhibition of NF-kappa B activation. Target genes of the NF-kappa B pathway, such as interleukin-6, were correspondingly down-regulated during bacterial infection with Salmonella expressing AvrA. AvrA also deubiquitinates and thus blocks degradation of beta-catenin. Target genes of the beta-catenin pathway, such as c-myc and cyclinD1, were correspondingly up-regulated with AvrA expression. increased beta-catenin further negatively regulates the NF-kappa B pathway. Our findings suggest an important role for AvrA in regulating host inflammatory responses through NF-kappa B and beta-catenin pathways.