去泛素化酶USP47调控TRAF6在炎症性肠病中的作用

Ubiquitin-specific proteases (USPs) are an important class of protein deubiquitination-modifying enzymes. Many members of the USP family are closely related to the development of inflammatory responses. Increased incidence of inflammatory bowel disease, defects in traditional therapies, and heavy medical expenses have prompted researchers to explore more molecular mechanisms. We found that deubiquitinating enzyme USP47 has a function of inhibiting inflammation in inflammatory bowel disease (IBD). In the USP47 knockout mice, the expression of inflammatory cytokines in the gut of the mice was higher than that of the wild-type mice under physiological conditions, showing mild enteritis. USP47 knockout mice had poor tolerance after feeding with dextran sulfate (DSS).The expression of USP47 was significantly lower in colonic inflammatory lesions than in non-inflammatory sites in IBD patients. Preliminary studies have shown that USP47 binds to TRAF6 in HeLa and HEK293T cells and is able to remove TRAF6 ubiquitination in vitro. Based on these important findings, USP47 knockout mice were used to study the site of USP47 expression and function in immune cells or intestinal epithelial cells. Furthermore, the mechanism of USP47 inhibiting inflammation was further confirmed. Pathogenesis research to provide new insights for the development of new strategies for treatment of IBD provide an important foundation.

泛素化特异蛋白酶（USPs）是一类重要的蛋白质去泛素化修饰酶，与炎症反应的发生密切相关。炎症性肠病（IBD）的发病率上升和传统疗法的缺陷等问题促使研究人员探索更多的分子机制。我们发现去泛素化酶USP47在炎症性肠病中具有抑制炎症发生的功能。USP47敲除小鼠在生理条件下肠道炎症因子的表达高于野生型小鼠，表现出轻度肠炎，当喂食葡聚糖硫酸钠（DSS）后，其耐受能力很差。临床病人结肠炎症部位USP47的表达明显低于非炎症部位。初步机制表明USP47在工具细胞中与肿瘤坏死因子受体相关因子6 (TRAF6) 相互结合，并能够在体外去泛素化TRAF6。本项目拟在这些发现的基础上，应用USP47基因敲除小鼠研究USP47表达的部位以及在免疫细胞或肠道上皮细胞中维持肠道稳态的功能，并进一步确定USP47抑制炎症的机制，可望为IBD的发病机制研究提供新的见解，为研发治疗IBD新策略提供重要基础。

炎症性肠病（IBD）的发病机制复杂，探究相关新的发病机制对于治疗具有重要指导作用。去泛素化酶具有调控蛋白稳定或定位而改变蛋白活性的功能，与炎症的发生密切相关。我们利用Usp47基因敲除小鼠发现Usp47对葡聚糖硫酸钠盐诱导的小鼠急性及慢性结肠炎具有保护作用，进一步的研究表明肠道上皮中的Usp47起到主要的功能。肠道微生物调控的稳态对于Usp47调控肠道炎症具有重要的作用，并且我们通过一系列的实验发现USP47在肠道上皮细胞中通过调节TRAF6的去泛素化而抑制NF-κB的活性进而抑制炎症。临床IBD标本显示炎症部位USP47的表达量显著降低，并且与炎症的程度具有相关性。USP47在肠道中调控炎症的功能丰富了IBD发病机制的研究，从蛋白水平及翻译后修饰出发，为IBD的治疗提供指导作用。