State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China; Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Liangzhu Laboratory, Zhejiang University, Hangzhou 310012, China
Puqi Wu
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China
Hao Liang
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China
Yu-Ze Xie
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China
Bo-Xin Zhang
Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Liangzhu Laboratory, Zhejiang University, Hangzhou 310012, China
Cai-Ling He
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China
Cong-Rong Yang
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China
Hongda Li
Institute for Brain Science and Disease, Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing 400016, China
Wei Mo
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China; Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Liangzhu Laboratory, Zhejiang University, Hangzhou 310012, China; Department of Immunology, School of Basic Medical Science, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310012, China; Institute for Brain Science and Disease, Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing 400016, China; Corresponding author
Zhang-Hua Yang
Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Liangzhu Laboratory, Zhejiang University, Hangzhou 310012, China; Corresponding author
Summary: ZBP1 is an interferon (IFN)-induced nucleic acid (NA) sensor that senses unusual Z-form NA (Z-NA) to promote cell death and inflammation. However, the mechanisms that dampen ZBP1 activation to fine-tune inflammatory responses are unclear. Here, we characterize a short isoform of ZBP1 (referred to as ZBP1-S) as an intrinsic suppressor of the inflammatory signaling mediated by full-length ZBP1. Mechanistically, ZBP1-S depresses ZBP1-mediated cell death by competitive binding with Z-NA for Zα domains of ZBP1. Cells from mice (Ripk1D325A/D325A) with cleavage-resistant RIPK1-induced autoinflammatory (CRIA) syndrome are alive but sensitive to IFN-induced and ZBP1-dependent cell death. Intriguingly, Ripk1D325A/D325A cells die spontaneously when ZBP1-S is deleted, indicating that cell death driven by ZBP1 is under the control of ZBP1-S. Thus, our findings reveal that alternative splicing of Zbp1 represents autogenic inhibition for regulating ZBP1 signaling and indicate that uncoupling of Z-NA with ZBP1 could be an effective strategy against autoinflammations.
