中國(guó)人民解放軍軍事醫(yī)學(xué)科學(xué)院張學(xué)敏研究員帶領(lǐng)的課題組新近研究發(fā)現(xiàn)一種新的蛋白質(zhì)CUEDC2,，在NF-κB信號(hào)通路的負(fù)性調(diào)節(jié)機(jī)制中起重要作用。該項(xiàng)研究是在國(guó)家杰出青年科學(xué)基金（30525021）,、國(guó)家自然科學(xué)基金面上項(xiàng)目（30672357）及國(guó)家863計(jì)劃等基金資助下完成的,，其研究結(jié)果3月23日在線發(fā)表于《自然—免疫學(xué)》（Nature Immunology）上,。
NF-κB信號(hào)通路的快速激活對(duì)機(jī)體應(yīng)對(duì)微生物入侵是十分必要的，但其持續(xù)激活又能產(chǎn)生組織損傷,、器官衰竭甚至死亡,，近年更發(fā)現(xiàn)與癌癥發(fā)生和發(fā)展密切相關(guān)。因此,，闡明NF-κB信號(hào)通路的調(diào)節(jié)機(jī)制是當(dāng)前免疫和腫瘤生物學(xué)領(lǐng)域亟待解決的重要科學(xué)問題,。目前已知，IKK蛋白激酶復(fù)合體是調(diào)控NF-κB信號(hào)通路的核心環(huán)節(jié),，對(duì)于各種感染原和細(xì)胞因子（TNF或IL-1）等激活I(lǐng)KK的機(jī)制已被廣泛研究并清楚闡明,，然而，機(jī)體對(duì)IKK的負(fù)性調(diào)節(jié)過程至今仍不清楚,，影響我們對(duì)一些重要疾病發(fā)生機(jī)制的認(rèn)識(shí),。
張學(xué)敏課題組的研究人員發(fā)現(xiàn)一個(gè)新蛋白質(zhì)CUEDC2，通過與IKK結(jié)合抑制NF-κB的激活,。進(jìn)一步的實(shí)驗(yàn)還表明CUEDC2能夠介導(dǎo)GADD34/PP1（蛋白質(zhì)磷酸酶1和其調(diào)節(jié)亞基）到IKK復(fù)合物上,，并通過對(duì)PP1招募實(shí)現(xiàn)對(duì)IKK磷酸化和激活的抑制。重要的發(fā)現(xiàn)還有,，CUEDC2/IKK復(fù)合物的形成是受細(xì)胞因子動(dòng)態(tài)調(diào)控的,。IKK通過與CUEDC2形成復(fù)合物，一旦細(xì)胞外信號(hào)刺激時(shí),，如TNF（腫瘤壞死因子）,，IKK將從CUEDC2復(fù)合物中解離，通過TRAF2和RIP介導(dǎo)與TNF受體形成復(fù)合物進(jìn)而被磷酸化激活,。隨后IKK從受體復(fù)合體上解離,，再與CUEDC2結(jié)合并被滅活。上述發(fā)現(xiàn)推進(jìn)了對(duì)NF-κB通路滅活機(jī)制的認(rèn)識(shí),，為炎癥,、自身免疫疾病和腫瘤的治療研究提供了新的靶點(diǎn)和方向。（來源：國(guó)家自然科學(xué)基金委員會(huì) 徐巖英）
生物谷推薦原始出處：
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
Abstract
Toll-like receptor (TLR) signaling is pivotal to innate and adaptive immune responses and must be tightly controlled. The mechanisms of TLR signaling have been the focus of extensive studies. Here we report that the tripartite-motif protein TRIM30, a RING protein, was induced by TLR agonists and interacted with the TAB2-TAB3-TAK1 adaptor-kinase complex involved in the activation of transcription 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.
