MOE Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China.
Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Nat Cell Biol. 2019 Aug;21(8):1027-1040. doi: 10.1038/s41556-019-0352-z. Epub 2019 Jul 22.
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.
通过 cGAS-STING 途径感知细胞质 DNA 构成了广泛的先天免疫机制，用于监测细胞损伤和微生物入侵。逃避这种监测对于肿瘤发生至关重要，但这一过程在很大程度上仍未得到探索。在这里，我们表明受体酪氨酸激酶 HER2（也称为 ErbB-2 或 Neu）强烈抑制 cGAS-STING 信号转导，并阻止癌细胞产生细胞因子、进入衰老和凋亡。HER2 而非 EGFR 与 STING 强烈结合，并募集 AKT1（也称为 PKB）直接磷酸化 TBK1，从而阻止 TBK1-STING 结合和 TBK1 K63 连接的泛素化，从而减弱 STING 信号转导。出乎意料的是，我们观察到 DNA 感应强烈激活 HER2-AKT1 轴，导致负反馈。因此，HER2-AKT1 级联的遗传或药理学靶向增强了损伤诱导的细胞衰老和凋亡，并增强了 STING 介导的抗病毒和抗肿瘤免疫。因此，我们的发现揭示了致癌途径在先天免疫调节中的关键功能，并出人意料地将 HER2-AKT1 信号与细胞损伤和抗肿瘤免疫的监测联系起来。
