Department of Cell Biology, University of Miami Miller School of Medicine, Miami, Florida, USA.
J Virol. 2014 May;88(10):5328-41. doi: 10.1128/JVI.00037-14. Epub 2014 Mar 5.
STING (stimulator of interferon genes) is known to control the induction of innate immune genes in response to the recognition of cytosolic DNA species, including the genomes of viruses such as herpes simplex virus 1 (HSV-1). However, while STING is essential for protection of the host against numerous DNA pathogens, sustained STING activity can lead to lethal inflammatory disease. It is known that STING utilizes interferon regulatory factor 3 (IRF3) and nuclear factor κB (NF-κB) pathways to exert its effects, although the signal transduction mechanisms remain to be clarified fully. Here we demonstrate that in addition to the activation of these pathways, potent induction of the Jun N-terminal protein kinase/stress-activated protein kinase (JNK/SAPK) pathway was similarly observed in response to STING activation by double-stranded DNA (dsDNA). Furthermore, TANK-binding kinase 1 (TBK1) associated with STING was found to facilitate dsDNA-mediated canonical activation of NF-κB as well as IRF3 to promote proinflammatory gene transcription. The triggering of NF-κB function was noted to require TRAF6 activation. Our findings detail a novel dsDNA-mediated NF-κB activation pathway facilitated through a STING-TRAF6-TBK1 axis and suggest a target for therapeutic intervention to plausibly stimulate antiviral activity or, alternatively, avert dsDNA-mediated inflammatory disease.
The IKK complex, which is composed of two catalytic subunits, IKKα and IKKβ, has been suggested to be essential for the activation of canonical NF-κB signaling in response to various stimuli, including cytokines (e.g., interleukin-1α [IL-1α] and tumor necrosis factor alpha [TNF-α]), Toll-like receptor (TLR) ligands (e.g., lipopolysaccharide [LPS]), and dsRNAs derived from viruses, or a synthetic analog. STING has been identified as a critical signaling molecule required for the detection of cytosolic dsDNAs derived from pathogens and viruses. However, little is known about how cytosolic dsDNA triggers NF-κB signaling. In the present study, we demonstrate that TBK1, identified as an IKK-related kinase, may predominantly control the activation of NF-κB in response to dsDNA signaling via STING through the IKKαβ activation loop. Thus, our results establish TBK1 as a downstream kinase controlling dsDNA-mediated IRF3 and NF-κB signaling dependent on STING.
STING（干扰素基因刺激物）已知可控制先天免疫基因的诱导，以响应细胞溶质 DNA 种类的识别，包括单纯疱疹病毒 1（HSV-1）等病毒的基因组。然而，虽然 STING 对于宿主抵抗许多 DNA 病原体的保护至关重要，但持续的 STING 活性会导致致命的炎症性疾病。已知 STING 利用干扰素调节因子 3（IRF3）和核因子 kappaB（NF-κB）途径发挥作用，尽管信号转导机制仍有待充分阐明。在这里，我们证明除了这些途径的激活之外，双链 DNA（dsDNA）激活 STING 还同样观察到 Jun N-末端蛋白激酶/应激激活蛋白激酶（JNK/SAPK）途径的强烈诱导。此外，与 STING 相关的 TANK 结合激酶 1（TBK1）被发现有助于 dsDNA 介导的 NF-κB 以及 IRF3 的经典激活，以促进前炎性基因转录。NF-κB 功能的触发需要 TRAF6 的激活。我们的发现详细说明了一种新的 dsDNA 介导的 NF-κB 激活途径，该途径通过 STING-TRAF6-TBK1 轴介导，并提出了一种治疗干预的靶标，以合理地刺激抗病毒活性，或者相反，避免 dsDNA 介导的炎症性疾病。
由两个催化亚基 IKKα 和 IKKβ 组成的 IKK 复合物已被认为对于各种刺激（包括细胞因子（例如白细胞介素 1α[IL-1α]和肿瘤坏死因子 alpha[TNF-α]）、Toll 样受体（TLR）配体（例如脂多糖[LPS]）和病毒衍生的双链 RNA，或合成类似物）引发的经典 NF-κB 信号转导是必不可少的。STING 已被鉴定为一种关键信号分子，用于检测源自病原体和病毒的细胞溶质双链 DNA。然而，对于细胞质双链 DNA 如何触发 NF-κB 信号知之甚少。在本研究中，我们证明了 TBK1，作为一种 IKK 相关激酶，通过 STING 通过 IKKαβ 激活环可能主要控制 dsDNA 信号转导中 NF-κB 的激活。因此，我们的结果确立了 TBK1 作为控制 dsDNA 介导的 IRF3 和 NF-κB 信号的下游激酶，该信号依赖于 STING。
