ASFV pD345L protein negatively regulates NF-κB signalling by inhibiting IKK kinase activity.
ASFV pD345L protein negatively regulates NF-κB signalling by inhibiting IKK kinase activity.
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DOI：
10.1186/s13567-022-01050-z
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发表时间：
2022-04-23
影响因子：
4.4
通讯作者：
Dai, Jianjun
中科院分区：
文献类型：
--
作者：
Chen, Huan;Wang, Zhenzhong;Gao, Xiaoyu;Lv, Jiaxuan;Hu, Yongxin;Jung, Yong-Sam;Zhu, Shanyuan;Wu, Xiaodong;Qian, Yingjuan;Dai, Jianjun
NF-κB 通路是防御病毒感染（包括非洲猪瘟病毒 (ASFV) 感染）的重要信号级联。 ASFV 通过其自身的转录机制编码超过 151 种蛋白质，并具有逃避或破坏抗病毒先天免疫反应的强大能力。尽管其中一些病毒蛋白已被报道，但许多仍然未知。在这里，我们发现 pD345L（一种 ASFV 编码的 lambda 样核酸外切酶）通过阻断 IkappaB 激酶 (IKKα/β) 活性，充当 cGAS/STING 介导的 NF-κB 信号传导的抑制剂。具体来说，我们发现 pD345L 的过表达会抑制 cGAS/STING 诱导的 IFNβ 和 NF-κB 激活，导致 IFNβ 和多种促炎细胞因子（包括 IL-1α、IL-6、IL-8 和 TNFα）的转录减少。此外，我们还发现 pD345L 作用于 IKK 或其下游以及 p65 上游。重要的是，我们发现 pD345L 与 IKKα 的 KD 和 HLH 结构域以及 IKKβ 的 LZ 结构域相关，从而中断它们对下游底物 IκBα 的激酶活性。最后，我们发现 pD345L 介导的 NF-κB 信号传导抑制与其核酸外切酶活性无关。综合考虑这些结果，我们得出结论，pD345L 通过蛋白质-蛋白质相互作用阻断 IKKα/β 激酶活性，从而破坏 cGAS/STING 介导的 NF-κB 信号传导。
The NF-κB pathway is an essential signalling cascade in the defence against viral infections, including African swine fever virus (ASFV) infection. ASFV encodes more than 151 proteins via its own transcription machinery and possesses a great capacity to evade or subvert antiviral innate immune responses. Although some of these viral proteins have been reported, many remain unknown. Here, we show that pD345L, an ASFV-encoded lambda-like exonuclease, acts as an inhibitor of cGAS/STING-mediated NF-κB signalling by blocking the IkappaB kinase (IKKα/β) activity. Specifically, we showed that overexpression of pD345L suppresses cGAS/STING-induced IFNβ and NF-κB activation, resulting in decreased transcription of IFNβ and several proinflammatory cytokines, including IL-1α, IL-6, IL-8, and TNFα. In addition, we showed that pD345L acts at or downstream of IKK and upstream of p65. Importantly, we found that pD345L associates with the KD and HLH domains of IKKα and the LZ domain of IKKβ and thus interrupts their kinase activity towards the downstream substrate IκBα. Finally, we showed that pD345L-mediated inhibition of NF-κB signalling was independent of its exonuclease activity. Considering these results collectively, we concluded that pD345L blocks IKKα/β kinase activity via protein–protein interactions and thus disrupts cGAS/STING-mediated NF-κB signalling.
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DOI：
10.1084/jem.20161867
发表时间：
2017-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Diamanti MA;Gupta J;Bennecke M;De Oliveira T;Ramakrishnan M;Braczynski AK;Richter B;Beli P;Hu Y;Saleh M;Mittelbronn M;Dikic I;Greten FR
通讯作者：
Greten FR
影响因子：
5.4
作者：
Afonso, CL;Piccone, ME;Rock, DL
通讯作者：
Rock, DL
影响因子：
3.7
作者：
Carrascosa, AL;Bustos, MJ;Revilla, Y
通讯作者：
Revilla, Y
影响因子：
5.4
作者：
Garcia-Belmonte, Raquel;Perez-Nunez, Daniel;Revilla, Yolanda
通讯作者：
Revilla, Yolanda
影响因子：
4.4
作者：
Granja, Aitor G.;Perkins, Neil D.;Revilla, Yolanda
通讯作者：
Revilla, Yolanda