Abstract：
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.
摘要：
ZBP1是干扰素（IFN）诱导的核酸（NA）传感器，可感应异常的Z型NA（Z-NA）以促进细胞死亡和炎症。然而,抑制ZBP1激活以微调炎症反应的机制尚不清楚.这里,我们将ZBP1的短同种型(称为ZBP1-S)描述为由全长ZBP1介导的炎症信号的内在抑制物。机械上,ZBP1-S通过与Z-NA竞争性结合ZBP1的Zα结构域来抑制ZBP1介导的细胞死亡。来自具有切割抗性RIPK1诱导的自身炎症(CRIA)综合征的小鼠(Ripk1D325A/D325A)的细胞是存活的,但对IFN诱导的和ZBP1依赖性细胞死亡敏感。有趣的是，当ZBP1-S缺失时，Ripk1D325A/D325A细胞自发死亡，表明由ZBP1驱动的细胞死亡处于ZBP1-S的控制之下。因此，我们的研究结果表明，Zbp1的可变剪接代表了调节ZBP1信号的自体抑制，并表明Z-NA与ZBP1的解偶联可能是对抗自身炎症的有效策略。
