HER2 recruits AKT1 to disrupt STING signalling and suppress antiviral defence and antitumour immunity.
Shiying WuQian ZhangFei ZhangFansen MengShengduo LiuRuyuan ZhouQingzhe WuXinran LiLi ShenJun HuangJun QinSongying OuyangZong-Ping XiaHai SongXin-Hua FengJian ZouPing-Long XuPublished in: Nature cell biology (2019)
Sensing cytosolic DNA through the cGAS-STING pathway constitutes a widespread innate immune mechanism to monitor cellular damage and microbial invasion. Evading this surveillance is crucial in tumorigenesis, but the process remains largely unexplored. Here, we show that the receptor tyrosine kinase HER2 (also known as ErbB-2 or Neu) potently inhibits cGAS-STING signalling and prevents cancer cells from producing cytokines, entering senescence and undergoing apoptosis. HER2, but not EGFR, associates strongly with STING and recruits AKT1 (also known as PKB) to directly phosphorylate TBK1, which prevents the TBK1-STING association and TBK1 K63-linked ubiquitination, thus attenuating STING signalling. Unexpectedly, we 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 enhances STING-mediated antiviral and antitumour immunity. Thus, our findings reveal a critical function of the oncogenic pathway in innate immune regulation and unexpectedly connect HER2-AKT1 signalling to the surveillance of cellular damage and antitumour immunity.
Keyphrases
- tyrosine kinase
- innate immune
- signaling pathway
- oxidative stress
- cell proliferation
- epidermal growth factor receptor
- public health
- small cell lung cancer
- dna damage
- endothelial cells
- endoplasmic reticulum stress
- cell death
- gene expression
- cell free
- microbial community
- genome wide
- transcription factor
- drug delivery
- nucleic acid