A ZBP1 isoform blocks ZBP1-mediated cell death

• Published in: Cell reports (Cambridge) Vol. 43; no. 5; p. 114221
• Main Authors: Cai, Zhi-Yu, Wu, Puqi, Liang, Hao, Xie, Yu-Ze, Zhang, Bo-Xin, He, Cai-Ling, Yang, Cong-Rong, Li, Hongda, Mo, Wei, Yang, Zhang-Hua
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.05.2024; Elsevier
• Subjects: Alternative Splicing - genetics; Animals; Cell Death; CP: Cell biology; CP: Molecular biology; HEK293 Cells; Humans; Inflammation - metabolism; Inflammation - pathology; Mice; Mice, Inbred C57BL; Protein Isoforms - genetics; Protein Isoforms - metabolism; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Signal Transduction; Z-NA; ZBP1; ZBP1-S; Zα domain; ZBP1; ZBP1-S; cell death; CP: Cell biology; CP: Molecular biology; Zα domain; Z-NA
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114221

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. [Display omitted] •ZBP1 short isoform is expressed synchronously with ZBP1•ZBP1 short isoform counteracts ZBP1-mediated cell death•ZBP1-S suppresses ZBP1 signaling in a Zα domain-dependent manner•ZBP1-S prevents the autoactivation of ZBP1 in Ripk1D325A/D325A cells The intrinsic mechanisms that dampen ZBP1 activation to fine-tune inflammatory responses are poorly understood. Cai et al. characterize a short isoform of ZBP1 (ZBP1-S) that acts as a suppressor via its Zα domains to counteract cell death mediated by full-length ZBP1, thus revealing an autogenic inhibition mechanism for regulating ZBP1 signaling.