九乡新闻网黄古林藤席怎么样:Nature Immunology：NF-κB通路灭活机制新进展 - 生物研究-生物谷
来源：百度文库 编辑：九乡新闻网 时间：2024/04/27 21:53:03
NF-κB信号通路的快速激活对机体应对微生物入侵是十分必要的，但其持续激活又能产生组织损伤、器官衰竭甚至死亡，近年更发现与癌症发生和发展密切相关。因此，阐明NF-κB信号通路的调节机制是当前免疫和肿瘤生物学领域亟待解决的重要科学问题。目前已知，IKK蛋白激酶复合体是调控NF-κB信号通路的核心环节，对于各种感染原和细胞因子（TNF或IL-1）等激活IKK的机制已被广泛研究并清楚阐明，然而，机体对IKK的负性调节过程至今仍不清楚，影响我们对一些重要疾病发生机制的认识。
张学敏课题组的研究人员发现一个新蛋白质CUEDC2，通过与IKK结合抑制NF-κB的激活。进一步的实验还表明CUEDC2能够介导GADD34/PP1（蛋白质磷酸酶1和其调节亚基）到IKK复合物上，并通过对PP1招募实现对IKK磷酸化和激活的抑制。重要的发现还有，CUEDC2/IKK复合物的形成是受细胞因子动态调控的。IKK通过与CUEDC2形成复合物，一旦细胞外信号刺激时，如TNF（肿瘤坏死因子），IKK将从CUEDC2复合物中解离，通过TRAF2和RIP介导与TNF受体形成复合物进而被磷酸化激活。随后IKK从受体复合体上解离，再与CUEDC2结合并被灭活。上述发现推进了对NF-κB通路灭活机制的认识，为炎症、自身免疫疾病和肿瘤的治疗研究提供了新的靶点和方向。（来源：国家自然科学基金委员会 徐岩英）
生物谷推荐原始出处：
Nature Immunology 9, 369 - 377 (2008) Published online: 16 March 2008 | doi:10.1038/ni1577
TRIM30
negatively regulates TLR-mediated NF-
B activation by targeting TAB2 and TAB3 for degradation
Mude Shi1,6, Weiwen Deng1,6, Enguang Bi1, Kairui Mao1, Yongyong Ji1, Guomei Lin1, Xiaodong Wu1, Zhiyun Tao1, Zhenhu Li1, Xinfen Cai1, Shuhui Sun2, Charlie Xiang3 & Bing Sun1,4,5
AbstractToll-like receptor (TLR) signalingis pivotal to innate and adaptive immune responses and must be tightlycontrolled. The mechanisms of TLR signaling have been the focus ofextensive studies. Here we report that the tripartite-motif proteinTRIM30
,a RING protein, was induced by TLR agonists and interacted with theTAB2-TAB3-TAK1 adaptor-kinase complex involved in the activation oftranscription factor NF-
B. TRIM30 promoted the degradation of TAB2 and TAB3 and inhibited NF-B activation induced by TLR signaling. In vivo studies showed that transfected or transgenic mice overexpressing TRIM30 were more resistant to endotoxic shock. Consistent with that, in vivo 'knockdown' of TRIM30 mRNA by small interfering RNA impaired lipopolysaccharide-induced tolerance. Finally, expression of TRIM30 depended on NF-B activation. Our results collectively indicate that TRIM30 negatively regulates TLR-mediated NF-B activation by targeting degradation of TAB2 and TAB3 by a 'feedback' mechanism.