Zhang Qian, Meng Fansen, Chen Shasha, Plouffe Steven W, Wu Shiying, Liu Shengduo, Li Xinran, Zhou Ruyuan, Wang Junxian, Zhao Bin, Liu Jianming, Qin Jun, Zou Jian, Feng Xin-Hua, Guan Kun-Liang, Xu Pinglong
Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China.
Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, USA.
Nat Cell Biol. 2017 Apr;19(4):362-374. doi: 10.1038/ncb3496. Epub 2017 Mar 27.
The Hippo pathway senses cellular conditions and regulates YAP/TAZ to control cellular and tissue homeostasis, while TBK1 is central for cytosolic nucleic acid sensing and antiviral defence. The correlation between cellular nutrient/physical status and host antiviral defence is interesting but not well understood. Here we find that YAP/TAZ act as natural inhibitors of TBK1 and are vital for antiviral physiology. Independent of transcriptional regulation and through the transactivation domain, YAP/TAZ associate directly with TBK1 and abolish virus-induced TBK1 activation, by preventing TBK1 Lys63-linked ubiquitylation and the binding of adaptors/substrates. Accordingly, YAP/TAZ deletion/depletion or cellular conditions inactivating YAP/TAZ through Lats1/2 kinases relieve TBK1 suppression and boost antiviral responses, whereas expression of the transcriptionally inactive YAP dampens cytosolic RNA/DNA sensing and weakens the antiviral defence in cells and zebrafish. Thus, we describe a function of YAP/TAZ and the Hippo pathway in innate immunity, by linking cellular nutrient/physical status to antiviral host defence.
河马通路感知细胞状态并调节YAP/TAZ以控制细胞和组织的稳态，而TBK1在胞质核酸传感和抗病毒防御中起核心作用。细胞营养/物理状态与宿主抗病毒防御之间的相关性很有趣，但尚未得到充分了解。在这里，我们发现YAP/TAZ作为TBK1的天然抑制剂，对抗病毒生理至关重要。YAP/TAZ独立于转录调控并通过反式激活结构域直接与TBK1结合，通过阻止TBK1赖氨酸63连接的泛素化以及衔接子/底物的结合来消除病毒诱导的TBK1激活。因此，YAP/TAZ的缺失/消耗或通过Lats1/2激酶使YAP/TAZ失活的细胞状态可减轻TBK1的抑制并增强抗病毒反应，而转录无活性的YAP的表达会抑制胞质RNA/DNA传感并削弱细胞和斑马鱼中的抗病毒防御。因此，我们通过将细胞营养/物理状态与抗病毒宿主防御联系起来，描述了YAP/TAZ和河马通路在先天免疫中的功能。
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