On May 8, 2017, Dr. Fangfang Zhou’s group published an article entitled “YAP antagonizes innate antiviral immunity and is targeted for lysosomal degradation through IKKε-mediated phosphorylation” in Nature Immunology(IF:19.38). This study found that YAP blocked the dimerization and nuclear translocation of the transcription factor IRF3, and consequently inhibit the innate antiviral response. Furthermore, IKKε phosphorylated YAP and induced the degradation of YAP in lysosomes and relief of YAP-mediated inhibition of innate immunity.
The pathway of the kinase Hippo and transcription regulator YAP is involved in organ-size control and tissue homeostasis. Upon activation of the pathway, YAP is phosphorylated by the kinases LATS1 and LATS2, which results in its degradation via ubiquitin-proteasome pathway or its interaction with the adaptor 14-3-3 and retention in the cytoplasm. When Hippo signaling is off, YAP enters the nucleus, and induces a series of genes transcription, which enhance cell proliferation and migration. Dysregulation of Hippo-YAP signaling pathway is closely correlated with tumorigenesis.However, whether YAP has a role in the innate antiviral response remains unknown.
In this article, the researchers identified YAP as a negative regulator of innate immunity to RNA and DNA viruses. YAP interacted with IRF3 and impaired the formation of IRF3 dimers and translocation of IRF3 to the nucleus after viral stimulation. YAP deficiency potentiated the function of IRF3, the production of IFN-β and innate antiviral responses to RNA and DNA viruses both in vitro and in vivo. Moreover，YAP was phosphorylated at Ser403 and targeted for lysosome-mediated degradation by IKKε after viral stimulation, which abolished the YAP-mediated restriction of antiviral signaling. These findings not only identified YAP as a negative regulator of IRF3, but also found a new mechanism for regulating YAP degradation independently of Hippo and LATS.
Associate professor Shuai Wang is the first author. Feng Xie，Feng Chu，Zhengkui Zhang，Tong Dai，Liang Gao，Lin Wang，Li Ling, ect. are contributing authors. Prof. Fangfang Zhou (Soochow University) and Prof. Long Zhang (Zhejiang University) are the co-corresponding authors. This work was supported by a special program from Ministry of Science and Technology of China (2016YFA0502500 to L.Z.), the Chinese National Natural Science Funds (31571460 to F.Z., 31471315 and 31671457 to L.Z.), PCSIRT (IRT1075 to X.G.) and Jiangsu National Science Foundation (BK20150354 to F.Z.).