Zhang, QianMeng, FansenChen, ShashaPlouffe, Steven W.Wu, ShiyingLiu, ShengduoLi, XinranZhou, RuyuanWang, JunxianZhao, BinLiu, JianmingQin, JunZou, JianFeng, Xin-HuaGuan, Kun-LiangXu, Pinglong2017-12-052017Zhang, Q., F. Meng, S. Chen, S. W. Plouffe, S. Wu, S. Liu, X. Li, et al. 2017. “Hippo signaling governs cytosolic nucleic acid sensing through YAP/TAZ-mediated TBK1 blockade.” Nature cell biology 19 (4): 362-374. doi:10.1038/ncb3496. http://dx.doi.org/10.1038/ncb3496.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34491997The 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 defense. The correlation between cellular nutrient/physical status and host antiviral defense 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 transactivation domain, YAP/TAZ associate directly with TBK1 and abolish virus-induced TBK1 activation, by preventing TBK1 K63-linked ubiquitination and adaptors/substrates binding. 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 defense 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 defense.en-USHippo pathwayYAP/TAZTBK1antiviral responsehost defenseJournal Article2017-12-0510.1038/ncb3496