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腾讯登录MCB:中科院健康所研究人员揭示IL-17信号通路调控新机制
| 导读 | 白介素-17（IL-17）是一个重要的促炎症细胞因子，由辅助性T细胞（Th17）及先天性免疫细胞等分泌，在多种炎性反应及自身免疫性疾病病理过程中发挥关键作用。IL-17受体（IL-17R）通过信号转导复合体IL-17R-Act1-TRAF6激活下游NF-kB、JNK等信号通路。然而，该信号通路的调控机制还有待深入阐明。博士生瞿芳芳，高汉超等在钱友存研究员的指导下研究发现IKK相关激酶（TBK1和I... |
白介素-17（IL-17）是一个重要的促炎症细胞因子，由辅助性T细胞（Th17）及先天性免疫细胞等分泌，在多种炎性反应及自身免疫性疾病病理过程中发挥关键作用。IL-17受体（IL-17R）通过信号转导复合体IL-17R-Act1-TRAF6激活下游NF-kB、JNK等信号通路。然而，该信号通路的调控机制还有待深入阐明。博士生瞿芳芳，高汉超等在钱友存研究员的指导下研究发现IKK相关激酶（TBK1和IKKi）以冗余方式直接磷酸化Act1，致使Act1与TRAF6的结合能力减弱，从而抑制IL-17诱导NF-kB激活。进一步研究发现，TRAF6通过介导TBK1的激活以及IKK相关激酶与Act1的相互作用，参与IL-17诱导的Act1的磷酸化；而TRAF3，作为抗病毒反应中IKK相关激酶的上游的关键衔接蛋白，不参与IL-17诱导的ACT1磷酸化。该研究发现并阐明了IL-17激活NF-kB通路中新的调控机制，即Act1-TRAF6-TBK1/IKKi-Act1负反馈循环调控，为IL-17相关疾病治疗提供了新的潜在靶点。
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该项目得到了国家自然科学基金，国家科技部，中国科学院和上海市科委的资助。
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<img src="http://www.bioon.com/biology/UploadFiles/201208/2012082111043298.bmp" alt="" width="134" height="178" border="0" />
<a title="" href="http://mcb.asm.org/content/early/2012/07/25/MCB.00268-12.long">doi:10.1128/MCB.00268-12</a>
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<br/><strong>TRAF6 dependent Act1 phosphorylation by the IKK-related kinases suppresses IL-17-induced NF-κB activation</strong><br/>
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
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<br/>来源：中科院上海生命科学院
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该项目得到了国家自然科学基金，国家科技部，中国科学院和上海市科委的资助。
<div>
<div>
<img src="http://www.bioon.com/biology/UploadFiles/201208/2012082111043298.bmp" alt="" width="134" height="178" border="0" />
<a title="" href="http://mcb.asm.org/content/early/2012/07/25/MCB.00268-12.long">doi:10.1128/MCB.00268-12</a>
PMC:
PMID:
</div>
<div>
<br/><strong>TRAF6 dependent Act1 phosphorylation by the IKK-related kinases suppresses IL-17-induced NF-κB activation</strong><br/>
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
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<br/>来源：中科院上海生命科学院
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