白介素-17（IL-17）是一個(gè)重要的促炎癥細(xì)胞因子,，由輔助性T細(xì)胞（Th17）及先天性免疫細(xì)胞等分泌，在多種炎性反應(yīng)及自身免疫性疾病病理過(guò)程中發(fā)揮關(guān)鍵作用,。IL-17受體（IL-17R）通過(guò)信號(hào)轉(zhuǎn)導(dǎo)復(fù)合體IL-17R-Act1-TRAF6激活下游NF-kB、JNK等信號(hào)通路,。然而,，該信號(hào)通路的調(diào)控機(jī)制還有待深入闡明。博士生瞿芳芳,，高漢超等在錢(qián)友存研究員的指導(dǎo)下研究發(fā)現(xiàn)IKK相關(guān)激酶（TBK1和IKKi）以冗余方式直接磷酸化Act1,，致使Act1與TRAF6的結(jié)合能力減弱，從而抑制IL-17誘導(dǎo)NF-kB激活,。進(jìn)一步研究發(fā)現(xiàn),，TRAF6通過(guò)介導(dǎo)TBK1的激活以及IKK相關(guān)激酶與Act1的相互作用，參與IL-17誘導(dǎo)的Act1的磷酸化,；而TRAF3,，作為抗病毒反應(yīng)中IKK相關(guān)激酶的上游的關(guān)鍵銜接蛋白，不參與IL-17誘導(dǎo)的ACT1磷酸化,。該研究發(fā)現(xiàn)并闡明了IL-17激活NF-kB通路中新的調(diào)控機(jī)制,，即Act1-TRAF6-TBK1/IKKi-Act1負(fù)反饋循環(huán)調(diào)控，為IL-17相關(guān)疾病治療提供了新的潛在靶點(diǎn),。
該項(xiàng)目得到了國(guó)家自然科學(xué)基金,，國(guó)家科技部，中國(guó)科學(xué)院和上海市科委的資助,。（生物谷Bioon.com）
doi:10.1128/MCB.00268-12
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TRAF6 dependent Act1 phosphorylation by the IKK-related kinases suppresses IL-17-induced NF-κB activation
Qu F, Gao H, Zhu S, Shi P, Zhang Y, Liu Y, Jallal B, Yao Y, Shi Y, Qian Y.
Interleukin 17 (IL-17) is critically involved in the pathogenesis of various inflammatory disorders. IL-17 receptor (IL-17R) proximal signaling complex (IL-17R-Act1-TRAF6) is essential for IL-17 mediated NF-κB activation while IL-17-mediated mRNA stability is TRAF6 independent. Recently, IKKi has been identified to phosphorylate Act1 on Ser 311 to mediate IL-17-induced mRNA stability. Here we show TBK1, the other IKK-related kinase, directly phosphorylated Act1 on three other Ser sites to suppress IL-17R mediated NF-κB activation. IL-17 stimulation activated TBK1 and induced its association with Act1. IKKi also phosphorylated Act1 on the three serine sites and played a redundant role with TBK1 in suppressing IL-17-induced NF-κB activation. Act1 phosphorylation on the three sites inhibited its association with TRAF6 and consequently NF-κB activation in IL-17R signaling. Interestingly, TRAF6 but not TRAF3 which is the upstream adaptor of the IKK related kinases in antiviral signaling, was critical for IL-17 induced Act1 phosphorylation. TRAF6 was essential for IL-17-induced TBK1 activation, its association with Act1, and consequent Act1 phosphorylation. Our findings define a new role for the IKK-related kinases in suppressing IL-17-mediated NF-κB activation through TRAF6 dependent Act1 phosphorylation
