Pinglong Xu Lab, Nature Cell Biology: Hippo signalling governs cytosolic nucleic acid sensing through YAP/TAZ-mediated TBK1 blockade

编辑: Date:2019/07/22

On July 22nd 2019, Xu laboratory published the research article in Nature Cell Biology entitled “HER2 recruits AKT1 to disrupt STING signalling and suppress antiviral defense and antitumor immunity”, which describes key functions of the classical oncogenic HER2-AKT pathway in DNA innate immune sensing as well as the antiviral and antitumor immunity.

Sensing cytosolic DNA through the cGAS-STING pathway constitutes a widespread innate immune mechanism to monitor cellular damage and microbe invasion. Evading this surveillance is crucial in tumorigenesis, but the process remains largely unexplored. Here, Xu laboratory found that receptor tyrosine kinase HER2/ErbB-2/Neu potently inhibits cGAS-STING signaling and prevents cancer cells from cytokine production, entering senescence, and undergoing apoptosis. HER2, but not EGFR, associates strongly with STING and recruits AKT1/PKB to directly phosphorylate TBK1, which preventing the TBK1-STING association and TBK1 K63-linked ubiquitination and thus attenuating STING signaling. Unexpectedly, Xu laboratory observed that DNA sensing robustly activates the HER2-AKT1 axis, resulting in negative feedback. Accordingly, genetic or pharmacological targeting of the HER2-AKT1 cascade augments damage-induced cellular senescence and apoptosis, and governs STING-mediated antiviral and antitumor immunity. Thus, findings from Xu laboratory reveal a critical function of the oncogenic pathway in innate immune regulation and unexpectedly connect HER2-AKT1 signaling to surveillance of cellular damage and antitumor immunity.

Drs. Shiying Wu and Qian Zhang and doctor candidate Fei Zhang in Xu laboratory are the first authors, and Dr. Pinglong Xu is the corresponding author of this research article. The study was accomplished in Life Sciences Institute (LSI) at Zhejiang University, collaborated by Drs. Jian Zou, Xin-Hua Feng, Jun Qin, Jun Huang, Hai Song and other colleagues, and sponsored by the NSFC Projects, the MOST 973 plan and the National 1000 Young Talents Program.

The classical oncogenic pathway HER2-AKT suppresses cGAS-STING signaling-mediated DNA innate sensing, as well as antiviral immunity and antitumor immunity.