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Open Access Publications from the University of California

Hippo signalling governs cytosolic nucleic acid sensing through YAP/TAZ-mediated TBK1 blockade.

  • Author(s): 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
  • et al.

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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.

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