LATS1 is a central signal transmitter for achieving full type-I interferon activity
Yibo Zuo, Jiuyi He, Siying Liu, Ying Xu, Jin Liu, Caixia Qiao, Lichao Zang, Wenhuan Sun, Yukang Yuan, Hongguang Zhang, Xiangjie Chen, Lincong Jin, Ying Miao, Fan Huang, Tengfei Ren, Jun Wang, Feng Qian, Chuanwu Zhu, Wei Zhang, Yaobo Liu, Guoqiang Xu, Feng Ma, Hui Zheng
Abstract
Interferons (IFNs) have broad-spectrum antiviral activity to resist virus epidemic. However, IFN antiviral efficacy needs to be greatly improved. Here, we reveal that LATS1 is a vital signal transmitter governing full type-I IFN (IFN-I) signaling activity. LATS1 constitutively binds with the IFN-I receptor IFNAR2 and is rapidly tyro-phosphorylated by Tyk2 upon IFN-I engagement. Tyro-phosphorylation of LATS1 promotes LATS1 activation and YAP degradation, thereby promoting IFN-mediated antiproliferation activity. Moreover, activated LATS1 translocates into the nucleus and induces CDK8-Ser62 phosphorylation, which in turn phosphorylates STAT1 at Ser 727 and induces full IFN-I antiviral activity. LATS1 deficiency restricts in vivo IFN-I signaling and attenuates host antiviral immune response. Our study identifies IFN-I as a previously unidentified extracellular diffusible ligand signal for activation of the Hippo core LATS1 pathway and reveals Tyk2-LATS1-CDK8 as a complete signaling cascade controlling full IFN-I activity.