β-Arrestin调控Toll样受体—白介素1受体的信号转导
发布时间：2018-11-01 11:25
【摘要】：Toll样受体-白介素1受体(TLR-IL-1R)信号转导对于宿主的免疫应答是很重要的,但是TLR-IL-1R过度或者不适当的激活都会对机体造成损害,因此TLR-IL-1R信号必须被很精细地调控。肿瘤坏死因子受体活化因子6 (TRAF6)是介导TLR-IL-1R信号传递的重要分子,并导致下游的转录因子核因子-κB(NF-κB)和激活蛋白-1(AP-1)的激活,这两种转录因子能够激活天然免疫反应。β抑制蛋白(β-arrestin)是一类多功能的蛋白,其经典的功能是介导细胞膜表面各种类型受体的脱敏和内吞。除此以外,β-arrestin还可以结合其它信号分子,调节后者的磷酸化、泛素化或者细胞内定位等等,从而调控相应的信号通路。我们的研究发现,在TLR-IL-1R信号激活下β-arrestin可以直接结合TRAF6。β-Arrestin结合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的小鼠成纤维细胞中TRAF6的自身泛素化、NF-κB抑制蛋白激酶(IKK)活性和有丝分裂原激活的蛋白激酶(MAPK)活性都较野生型细胞增强。在多种致病分子的刺激下,缺失β-arrestin2的小鼠巨噬细胞能够比对照野生型细胞产生更多的炎症因子。缺失β-arrestin2的小鼠,用内毒素刺激后,也比对照野生型小鼠产生更多的炎症因子,且对内毒素休克更为敏感。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,
【学位授予单位】：中国科学院研究生院（上海生命科学研究院）
【学位级别】：博士
【学位授予年份】：2006
【分类号】：R392
[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,
【学位授予单位】：中国科学院研究生院（上海生命科学研究院）
【学位级别】：博士
【学位授予年份】：2006
【分类号】：R392
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