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

Abstract

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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Figure 1: Activation of Hippo signalling enhances cytosolic RNA/DNA sensing.
Figure 2: YAP/TAZ attenuate cytosolic RNA/DNA sensing and antiviral responses.
Figure 3: YAP and TAZ abrogate TBK1 activation independent of their transcriptional potential.
Figure 4: YAP and TAZ associate with and disrupt the TBK1 signalling complex and Lys63 ubiquitylation.
Figure 5: YAP abolishes TBK1 activity through its C-terminal transactivation domain.
Figure 6: Lats1/2 relieve the association and inhibition of TBK1 by YAP/TAZ.
Figure 7: YAP/TAZ control host antiviral defence in cells.
Figure 8: YAP attenuates cytosolic nucleic acid sensing and antiviral defence in zebrafish.

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Acknowledgements

We are grateful to Z. J. Chen (UT Southwestern Medical Center, Dallas, USA), for gVSV virus, J. Han (Xiamen University, Xiamen, China) for glHSV-1 virus, and Z. Xia, Y. Huang, X. Wang and J. Jin (all Zhejiang University, China) for reagents. This research was partly supported by MoST 973 Plan (2015CB553800), NSFC Project (81472665, 91540205 and 31571447), CPSF (581220-X91602), DoD grant (1W81XWH-15-1-0650), NIH (R01GM051586, R35CA196878, and R21CA209007), and Project 985 and the Fundamental Research Funds for the Central Universities to the Life Sciences Institute at Zhejiang University. P.X. is a scholar in the National 1000 Young Talents Program.

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Authors and Affiliations

Authors

Contributions

Q.Z. and F.M. carried out most experiments. S.C., S.W., S.L., R.Z., J.W. and J.Q. contributed to several experiments, S.W.P., X.L., B.Z., J.L., J.Z., X.-H.F. and K.-L.G. helped with data analyses and discussions. P.X. conceived the study and experimental design and wrote the manuscript.

Corresponding author

Correspondence to Pinglong Xu.

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Competing interests

K.-L.G. co-founded but receives no direct financial support from Vivace Therapeutics. All other authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 The responses of Lats1/2 dKO cells and other signaling pathways to energy/nutrient stress.

Related to Fig. 1. (A) Serum starvation failed to significantly potentiate the Wnt, Hedgehog, and TGF-β/Smad signaling, measured by indicated reporters and stimulated by LiCl treatment, Gli1, or activated type I TGF-β receptor, respectively. n = 3 independent experiments. Mean ± s.e.m. P > 0.05, by ANOVA test and Bonferroni correction. (B) Lats1/2 dKO HEK293A cells did not respond to glucose stress (2-DG treatment) or nutrient stress (serum starvation) to activate YAP Ser127 phosphorylation or to cause TAZ degradation. Unprocessed images of blots are shown in Supplementary Fig. 6. Statistics source data are provided in Supplementary Table 1.

Supplementary Figure 2 YAP/TAZ inhibit signaling pathways mediated by MAVS, TBK1, TRIF and MyD88.

Related to Fig. 2. (A) and (B): Ectopic expression of YAP or TAZ inhibited IRF3 transactivation that was stimulated by TBK1 (A) or IKKɛ (B), in a dose-dependent manner. n = 3 independent experiments. P < 0.001, by ANOVA test and Bonferroni correction. (C) IRF3 transactivation stimulated by MAVS was also boosted under siRNA-mediated depletion of YAP and/or TAZ. n = 3 independent experiments. Mean ± s.e.m.P < 0.001, by ANOVA test and Bonferroni correction. (D) siRNA-mediated knockdown of YAP or TAZ enhanced the activation of ectopically expressed TBK1. (E) and (F), Coexpression of YAP 6SA or TAZ suppressed the IRF3 responsiveness stimulated by TRIF cotransfection (E), or the NF-κB responsiveness stimulated by MyD88 cotransfection (F). n = 3 independent experiments. Mean ± s.e.m.P < 0.001, by ANOVA test and Bonferroni correction. (G) Endogenous YAP/TAZ proteins were abundant in HEK293, mouse embryonic fibroblasts (MEFs) and NMuMG epithelial cells, but were scarce in THP-1 monocytes and peritoneal macrophages (PMs). Unprocessed images of blots are shown in Supplementary Fig. 6. Statistics source data are provided in Supplementary Table 1.

Supplementary Figure 3 TBK1 modifies full-length and the transactivation domain of YAP in cells and in vitro.

Related to Fig. 5. (A) and B) TBK1-mediated modification of full-length (fl) or the transactivation domain (a.a. 291–488) of YAP was revealed by the evidently mobility shift of YAPs, occurred during coexpression in cells (A), or during an in vitro kinase assay with GST tagged YAPs expressed and purified from E.coli. Unprocessed images of blots are shown in Supplementary Fig. 6.

Supplementary Figure 4 VSV-induced translocation and TBK1 association of YAP/TAZ.

Related to Fig. 6. (A) VSV infection induced a translocation of endogenous YAP/TAZ from the nucleus to the cytoplasm in HaCaT cells, revealed by the nuclear/cytoplasmic fractionation and subsequent immunoblotting. (B) Individual mutations of five Serines (Ser61, Ser109, Ser127, Ser164, or Ser381) into Aspartate did not release YAP’s inhibition on TBK1 substantially. n = 3 independent experiments. Mean ± s.e.m. (C) Interactions between TBK1 and YAP 6SA or YAP mimetic with Ser127 phosphorylation was revealed by co-immunoprecipitation. Unprocessed images of blots are shown in Supplementary Fig. 6. Statistics source data are provided in Supplementary Table 1.

Supplementary Figure 5 YAP and Lats1/2 are involved in regulation of antiviral signaling and resistance.

Related to Fig. 7. (A) Treatment of the TBK1/IKKɛ inhibitor BX795 eliminated most inhibitory effect of YAP 6SA on antiviral defense, suggesting that this regulation is mainly through TBK1/IKKɛ. Scale bars, 100 μm. (B) Decreased levels of antiviral signaling stimulated by MAVS coexpression was observed in Lats1/2 dKO HEK293A cells by the IRF3-responsive reporter assay. n = 3 independent experiments. Mean ± s.e.m.P = 0.0017, by ANOVA test and Bonferroni correction. Unprocessed images of blots are shown in Supplementary Fig. 6. Statistics source data are provided in Supplementary Table 1.

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Zhang, Q., Meng, F., Chen, S. et al. Hippo signalling governs cytosolic nucleic acid sensing through YAP/TAZ-mediated TBK1 blockade. Nat Cell Biol 19, 362–374 (2017). https://doi.org/10.1038/ncb3496

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