Triggering endogenous Z-RNA sensing for anti-tumor therapy through ZBP1-dependent necroptosis
Tao Yang,
Guodong Wang,
Mingxiang Zhang,
Xiaohu Hu,
Qi Li,
Fenglin Yun,
Yingying Xing,
Xinyang Song,
Haibing Zhang,
Guohong Hu,
Youcun Qian
Affiliations
Tao Yang
CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Guodong Wang
CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Mingxiang Zhang
School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China
Xiaohu Hu
CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Qi Li
CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Fenglin Yun
CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Yingying Xing
CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Xinyang Song
State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
Haibing Zhang
CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Guohong Hu
CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Youcun Qian
CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China; Corresponding author
Summary: ZBP1 senses viral Z-RNAs to induce necroptotic cell death to restrain viral infection. ZBP1 is also thought to recognize host cell-derived Z-RNAs to regulate organ development and tissue inflammation in mice. However, it remains unknown how the host-derived Z-RNAs are formed and how these endogenous Z-RNAs are sensed by ZBP1. Here, we report that oxidative stress strongly induces host cell endogenous Z-RNAs, and the Z-RNAs then localize to stress granules for direct sensing by ZBP1 to trigger necroptosis. Oxidative stress triggers dramatically increase Z-RNA levels in tumor cells, and the Z-RNAs then directly trigger tumor cell necroptosis through ZBP1. Localization of the induced Z-RNAs to stress granules is essential for ZBP1 sensing. Oxidative stress-induced Z-RNAs significantly promote tumor chemotherapy via ZBP1-driven necroptosis. Thus, our study identifies oxidative stress as a critical trigger for Z-RNA formation and demonstrates how Z-RNAs are directly sensed by ZBP1 to trigger anti-tumor necroptotic cell death.
