The NF-κB/Rel family of transcription factors that play critical roles in a variety of cellular processes. Their production in the cell and physiological activation are tightly regulated. The proteasomal processing of inactive NF-κB1/p105 to active p50, with an anti-inflammatory role, is not well characterized. Here we show that ubiquitin ligase TRUSS is a mediator of transcriptional activation of anti-inflammatory cytokine IL-10 gene. Enforced expression of TRUSS led to enhanced IL-10 expression that could be inhibited in the presence of chemical inhibitors of NF-κB [BAY11–7082] and PI3K/Akt [LY249002] or after p65 overexpression. p50 was actively recruited on IL10 promoter in the presence of TRUSS but competed by p65 for binding. TRUSS facilitated the ubiquitination of NF-κB1/p105 and promoted its proteolytic processing to generate excess of p50. Our immune-histochemical studies confirmed enhanced expression of p105/p50 in the human HCC tumors. Further, the hepatic tumors of HCC patient as well as transgenic mice showed decreased levels of p50 as well as TRUSS and accumulation of p105. Thus, enhanced expression of IL-10 gene in the presence of TRUSS and regulation of NF-κB1/p105 processing could be an important regulatory mechanism for inflammatory response and tumorgenic transformation.

NF-κB/Rel 转录因子家族，在多种细胞过程中发挥关键作用。它们在细胞中的产生和生理激活受到严格调控。蛋白酶体将非活性 NF-κB1/p105 加工成具有抗炎作用的活性 p50，尚未得到很好的表征。在这里，我们表明泛素连接酶 TRUSS 是抗炎细胞因子 IL-10 基因转录激活的介质。TRUSS 的强制表达导致 IL-10 表达增强，在存在 NF-κB [BAY11-7082] 和 PI3K/Akt [LY249002] 化学抑制剂或 p65 过表达后，IL-10 表达可能被抑制。在 TRUSS 存在下，p50 在 IL10 启动子上被积极募集，但与 p65 竞争结合。TRUSS 促进了 NF-κB1/p105 的泛素化并促进其蛋白水解加工以产生过量的 p50。我们的免疫组织化学研究证实了 p105/p50 在人类 HCC 肿瘤中的表达增强。此外，HCC 患者和转基因小鼠的肝肿瘤显示 p50 水平降低以及 TRUSS 和 p105 积累。因此，在 TRUSS 存在下 IL-10 基因的增强表达和 NF-κB1/p105 加工的调节可能是炎症反应和致瘤性转化的重要调节机制。