文獻：NCB 揭示經典致癌通路HER2-AKT的天然免疫識別調控以及腫瘤免疫、感染免疫和細胞衰老功能

經典致癌通路HER2-AKT1抑制DNA天然免疫識別的分子機制和腫瘤免疫、病毒免疫功能。

Abstract

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.

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

來源：

http://lsi.zju.edu.cn/2019/0716/c25130a1300386/page.htm

本期編輯：蘇復

喜歡這篇文章嗎？立刻分享出去讓更多人知道吧！