Konno Hiroyasu, Yamamoto Takuya, Yamazaki Kohsuke, Gohda Jin, Akiyama Taishin, Semba Kentaro, Goto Hideo, Kato Atsushi, Yujiri Toshiaki, Imai Takahiko, Kawaguchi Yasushi, Su Bing, Takeuchi Osamu, Akira Shizuo, Tsunetsugu-Yokota Yasuko, Inoue Jun-ichiro
Division of Cellular and Molecular Biology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
PLoS One. 2009 May 25;4(5):e5674. doi: 10.1371/journal.pone.0005674.
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 kappaB (NF-kappaB) 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-kappaB 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-kappaB and IRF7, but not that of IRF3, was significantly impaired during RLH signaling in the absence of TRAF6. TGFbeta-activated kinase 1 (TAK1) and MEKK3, whose activation by TRAF6 during TLR signaling is involved in NF-kappaB activation, were not essential for RLH-mediated NF-kappaB activation. We also demonstrate that TRAF6-deficiency impaired cytosolic DNA-induced antiviral responses, and this impairment was due to defective activation of NF-kappaB and IRF7.
CONCLUSIONS/SIGNIFICANCE: 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.
作为对病毒感染的反应，先天性免疫系统识别病毒核酸，随后诱导促炎细胞因子和I型干扰素（IFN）的产生。Toll样受体7（TLR7）和TLR9分别在内体区室中检测病毒RNA和DNA，从而导致浆细胞样树突状细胞中核因子κB（NF-κB）和IFN调节因子（IRF）的激活。在这种TLR信号传导过程中，肿瘤坏死因子受体相关因子6（TRAF6）对于NF-κB的激活和I型IFN的产生至关重要。相比之下，RIG样解旋酶（RLH）作为胞质RNA传感器，对于常规树突状细胞、巨噬细胞和成纤维细胞中的抗病毒反应不可或缺。然而，TRAF6对胞质病毒核酸检测的贡献一直存在争议，并且TRAF6在IRF激活中的作用尚未得到充分探讨。
在此我们首次表明TRAF6在RLH信号传导中起关键作用。缺乏TRAF6导致RNA病毒感染后病毒复制增强以及IL-6和I型IFN的产生显著减少。在缺乏TRAF6的情况下，RLH信号传导过程中NF-κB和IRF7的激活显著受损，但IRF3的激活未受影响。TGFβ激活激酶1（TAK1）和MEKK3，其在TLR信号传导过程中由TRAF6激活参与NF-κB激活，对于RLH介导的NF-κB激活并非必需。我们还证明TRAF6缺陷会损害胞质DNA诱导的抗病毒反应，并且这种损害是由于NF-κB和IRF7的激活缺陷所致。
结论/意义：因此，TRAF6以不同于与TLR信号传导相关的方式介导由胞质病毒DNA和RNA触发的抗病毒反应。鉴于其在获得性免疫系统中涉及的各种受体信号传导中的关键作用，TRAF6代表了针对病毒感染的先天性和抗原特异性免疫反应中的关键分子。
