USP13调控IL-18诱导的NF-κB活化的分子机制研究

IL-18-induced NF-κB activation plays important roles in inflammation and immune response, while deregulation or excessive activation of the signaling events may lead to excessive immune response or autoimmune diseases. Thus, IL-18-triggered inflammatory response must be finely and tightly regulated. To identity additional molecules that regulate IL-18-induced NF-κB activation, we screened 10,000 expression clones by NF-κB reporter assay, and identified the ubiquitin-specific protease 13 (USP13) as a negative regulator. Overexpression of USP13 inhibited IL-18-triggered NF-κB activation, whereas knockdown of USP13 had the opposite effects. And coimmunoprecipitation experiment showed that USP13 specially interacted with IL-18R. This project will systematically investigate the function and molecular mechanisms of USP13 in IL-18-triggered inflammatory response on both cellular molecular and animal model levels. It will not only help to understand the regulations of IL-18-induced signaling pathway, but also provide potential targets for drug development against inflammatory diseases.

IL-18诱导转录因子NF-κB的激活在炎症反应和免疫应答中具有重要作用，但是其活性的失调会导致机体炎性疾病的发生。因此，IL-18诱导NF-κB的激活信号通路受到精细而严格的调控。申请人通过NF-κB报告基因实验筛选了10,000个cDNA表达克隆，发现去泛素化酶USP13显著抑制IL-18诱导的NF-κB激活，相反，USP13表达的下调则促进这一过程。免疫共沉淀实验表明，USP13特异性地结合IL-18受体IL-18R。本项目将通过细胞生物学、分子生物学等实验手段并利用基因敲除小鼠模型系统研究USP13在IL-18诱导的炎症反应中的功能和分子机制。该项目将有助于了解IL-18诱导NF-κB激活的信号转导分子机制，为炎性疾病的治疗和药物开发提供新的潜在靶标。

IL-6-STAT3信号通路在炎症相关癌变(IAC)中起重要作用。然而，该信号通路是如何被精细调节导致IAC的发生仍然是个谜。我们发现，质膜相关E3泛素连接酶MARCH3负调控由IL-6以及IL-6亚家族成员OSM诱导的STAT3激活。MARCH3与IL-6受体a链(IL-6Ra)及其辅助受体gp130发生相互作用。生化实验表明，在IL-6刺激下，MARCH3介导IL-6Ra的K401和gp130的K849位点发生多聚泛素化，导致其在溶酶体中降解。March3的缺失增加IL-6诱导的STAT3激活和各种细胞类型下游效应基因的诱导。March3的缺失加重了硫酸葡聚糖钠(DSS)诱导的STAT3激活、炎症细胞因子表达和结肠炎以及azoxymethane (AOM)/DSS诱导的小鼠结肠炎相关癌症。此外，MARCH3在人类结直肠癌组织中的表达下调，其低表达与多种不同癌症类型的低生存率相关。我们的研究结果表明，MARCH3是IL-6诱导的STAT3激活、炎症和炎症相关癌症发展的关键负调控因子。

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