TRAF6 establishes innate immune responses by activating NF-kappaB and IRF7 upon sensing cytosolic viral RNA and DNA.
TRAF6 establishes innate immune responses by activating NF-kappaB and IRF7 upon sensing cytosolic viral RNA and DNA.
复制标题
DOI：
10.1371/journal.pone.0005674
复制
发表时间：
2009-05-25
期刊：
影响因子：
3.7
通讯作者：
Inoue J
中科院分区：
文献类型：
--
作者：
Konno H;Yamamoto T;Yamazaki K;Gohda J;Akiyama T;Semba K;Goto H;Kato A;Yujiri T;Imai T;Kawaguchi Y;Su B;Takeuchi O;Akira S;Tsunetsugu-Yokota Y;Inoue J
作为对病毒感染的反应，先天免疫系统识别病毒核酸，然后诱导促炎细胞因子和I型干扰素(IFN)的产生。Toll样受体7(Toll-like Receptor 7，TLR7)和Toll样受体9(Toll-like Receptor 7，TLR9)分别在胞体内检测病毒核糖核酸和脱氧核糖核酸，导致浆细胞样树突状细胞中核因子κB(NF-κB)和干扰素调节因子(IRFs)的激活。在TLR信号转导过程中，肿瘤坏死因子受体相关因子6(TRAF6)对NF-κB的激活和I型干扰素的产生起着至关重要的作用。相反，RIG样解旋酶(RLHs)是胞质RNA传感器，对于传统的树突状细胞、巨噬细胞和成纤维细胞的抗病毒反应是不可或缺的。然而，TRAF6在检测胞质病毒核酸中的作用一直存在争议，而且TRAF6在IRF激活中的作用还没有得到充分的解决。在这里，我们首先展示了TRAF6在RLH信号转导中的关键作用。TRAF6的缺失导致病毒复制增强，感染RNA病毒后IL-6和I型IFN的产生显著减少。在没有TRAF6的情况下，在κ信号转导过程中，NF-TRAFB和IRF7的活性显著降低，而IRF3的活性不受影响。转化生长因子受体激活蛋白激活的蛋白1和3在β信号转导过程中被TRAF6激活，参与了NF-κB的激活，但它们对RLH介导的NF-κB激活不是必需的。我们还证明，TRAF6缺乏可以损害胞浆DNA诱导的抗病毒反应，这种损害是由于NF-κB和IRF7的缺陷激活所致。因此，TRAF6以一种不同于TLR信号通路的方式介导由胞浆病毒DNA和RNA触发的抗病毒反应。由于TRAF6在获得性免疫系统中涉及的各种受体的信号传递中发挥着重要作用，它是对抗病毒感染的先天和抗原特异性免疫反应中的关键分子。
In response to viral infection, the innate immune system recognizes viral nucleic acids and then induces production of proinflammatory cytokines and type I interferons (IFNs). Toll-like receptor 7 (TLR7) and TLR9 detect viral RNA and DNA, respectively, in endosomal compartments, leading to the activation of nuclear factor κB (NF-κB) and IFN regulatory factors (IRFs) in plasmacytoid dendritic cells. During such TLR signaling, TNF receptor-associated factor 6 (TRAF6) is essential for the activation of NF-κB and the production of type I IFN. In contrast, RIG-like helicases (RLHs), cytosolic RNA sensors, are indispensable for antiviral responses in conventional dendritic cells, macrophages, and fibroblasts. However, the contribution of TRAF6 to the detection of cytosolic viral nucleic acids has been controversial, and the involvement of TRAF6 in IRF activation has not been adequately addressed. Here we first show that TRAF6 plays a critical role in RLH signaling. The absence of TRAF6 resulted in enhanced viral replication and a significant reduction in the production of IL-6 and type I IFNs after infection with RNA virus. Activation of NF-κB and IRF7, but not that of IRF3, was significantly impaired during RLH signaling in the absence of TRAF6. TGFβ-activated kinase 1 (TAK1) and MEKK3, whose activation by TRAF6 during TLR signaling is involved in NF-κB activation, were not essential for RLH-mediated NF-κB activation. We also demonstrate that TRAF6-deficiency impaired cytosolic DNA-induced antiviral responses, and this impairment was due to defective activation of NF-κB and IRF7. Thus, TRAF6 mediates antiviral responses triggered by cytosolic viral DNA and RNA in a way that differs from that associated with TLR signaling. Given its essential role in signaling by various receptors involved in the acquired immune system, TRAF6 represents a key molecule in innate and antigen-specific immune responses against viral infection.
登录
查看更多内容
影响因子：
30.5
作者：
Buerckstuemmer, Tilmann;Baumann, Christoph;Superti-Furga, Giulio
通讯作者：
Superti-Furga, Giulio
影响因子：
4.4
作者：
Balachandran, Siddharth;Venkataraman, Thiagarajan;Barber, Glen N.
通讯作者：
Barber, Glen N.
影响因子：
5.4
作者：
Kato, Atsushi;Kiyotani, Katsuhiro;Nagai, Yoshiyuki
通讯作者：
Nagai, Yoshiyuki
影响因子：
30.5
作者：
Kawai, T;Takahashi, K;Akira, S
通讯作者：
Akira, S
影响因子：
4.4
作者：
Gohda, J;Matsumura, T;Inoue, J
通讯作者：
Inoue, J