【摘要】：Toll樣受體-白介素1受體(TLR-IL-1R)信號(hào)轉(zhuǎn)導(dǎo)對(duì)于宿主的免疫應(yīng)答是很重要的,但是TLR-IL-1R過度或者不適當(dāng)?shù)募せ疃紩?huì)對(duì)機(jī)體造成損害,因此TLR-IL-1R信號(hào)必須被很精細(xì)地調(diào)控。腫瘤壞死因子受體活化因子6 (TRAF6)是介導(dǎo)TLR-IL-1R信號(hào)傳遞的重要分子,并導(dǎo)致下游的轉(zhuǎn)錄因子核因子-κB(NF-κB)和激活蛋白-1(AP-1)的激活,這兩種轉(zhuǎn)錄因子能夠激活天然免疫反應(yīng)。β抑制蛋白(β-arrestin)是一類多功能的蛋白,其經(jīng)典的功能是介導(dǎo)細(xì)胞膜表面各種類型受體的脫敏和內(nèi)吞。除此以外,β-arrestin還可以結(jié)合其它信號(hào)分子,調(diào)節(jié)后者的磷酸化、泛素化或者細(xì)胞內(nèi)定位等等,從而調(diào)控相應(yīng)的信號(hào)通路。我們的研究發(fā)現(xiàn),在TLR-IL-1R信號(hào)激活下β-arrestin可以直接結(jié)合TRAF6。β-Arrestin結(jié)合TRAF6后,可以抑制TRAF6的泛素化和寡聚化,以及下游NF-κB和AP-1的激活。在脂多糖(LPS)的刺激下,缺失β-arrestin1和β-arrestin2的小鼠成纖維細(xì)胞中TRAF6的自身泛素化、NF-κB抑制蛋白激酶(IKK)活性和有絲分裂原激活的蛋白激酶(MAPK)活性都較野生型細(xì)胞增強(qiáng)。在多種致病分子的刺激下,缺失β-arrestin2的小鼠巨噬細(xì)胞能夠比對(duì)照野生型細(xì)胞產(chǎn)生更多的炎癥因子。缺失β-arrestin2的小鼠,用內(nèi)毒素刺激后,也比對(duì)照野生型小鼠產(chǎn)生更多的炎癥因子,且對(duì)內(nèi)毒素休克更為敏感。因此,通
[Abstract]:Toll like receptor-interleukin-1 receptor (TLR-IL-1R) signal transduction is very important for the host immune response, but excessive or inappropriate activation of TLR-IL-1R can damage the body. Therefore, the TLR-IL-1R signal must be carefully regulated. Tumor necrosis factor receptor activating factor 6 (TRAF6) is an important molecule that mediates TLR-IL-1R signal transduction, and leads to activation of nuclear factor 魏 B (NF- 魏 B) and activator protein-1 (AP-1) downstream. These two transcription factors can activate innate immune response. 尾-arrestin is a multifunctional protein whose classical function is to mediate the desensitization and endocytosis of various types of receptors on the surface of cell membrane. In addition, 尾-arrestin can bind to other signaling molecules and regulate phosphorylation, ubiquification or intracellular localization of the latter, thus regulating the corresponding signaling pathways. Our results show that 尾-arrestin can directly bind TRAF6. 尾-Arrestin to TRAF6, inhibit the ubiquitization and oligomerization of TRAF6 and the activation of NF- 魏 B and AP-1 downstream under the activation of TLR-IL-1R signal. Under the stimulation of lipopolysaccharide (LPS), the Ubiquitin of TRAF6 in mouse fibroblasts without 尾-arrestin1 and 尾-arrestin2 was found. NF- 魏 B inhibits the activity of protein kinase (IKK) and mitogen-activated protein kinase (MAPK). Under the stimulation of various pathogenetic molecules, murine macrophages without 尾-arrestin2 produced more inflammatory factors than wild-type cells. The mice without 尾-arrestin2 also produced more inflammatory factors and were more sensitive to endotoxin shock after endotoxin stimulation than the wild type mice. Therefore,
【學(xué)位授予單位】：中國科學(xué)院研究生院（上海生命科學(xué)研究院）
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2006
【分類號(hào)】：R392

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