Institute for Genetics, University of Cologne, D-50674, Cologne, Germany.
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, D-50931, Cologne, Germany.
EMBO J. 2024 Nov;43(21):5037-5056. doi: 10.1038/s44318-024-00238-7. Epub 2024 Sep 19.
Z-DNA-binding protein 1 (ZBP1) is an interferon-inducible sensor of Z-DNA and Z-RNA, which has emerged as a critical regulator of cell death and inflammation. ZBP1 binds Z-DNA and Z-RNA via its Zα domains, and signals by engaging RIPK3 and RIPK1 via its RIP homotypic interaction motifs (RHIMs). Here, we show that mice express an alternatively-spliced shorter ZBP1 isoform (ZBP1-S), which harbours the Zα domains but lacks the RHIMs, and acts as an endogenous inhibitor of the full-length protein (ZBP1-L). Mice and cells expressing only ZBP1-S are resistant to ZBP1-mediated cell death and inflammation. In contrast, cells lacking ZBP1-S show increased ZBP1-L-induced death compared to cells expressing both isoforms. Moreover, loss of the short isoform accelerates and exacerbates skin inflammation induced by ZBP1-mediated necroptosis of RIPK1-deficient keratinocytes, revealing an important physiological role of ZBP1-S. Mechanistically, ZBP1-S suppresses ZBP1-L-mediated cell death by binding to Z-nucleic acids via its Zα domains. Therefore, ZBP1-S acts as an endogenous inhibitor that competes with full-length ZBP1-L for binding Z-nucleic acid ligands to fine-tune ZBP1-mediated cell death and inflammation.
Z-DNA 结合蛋白 1（ZBP1）是一种干扰素诱导的 Z-DNA 和 Z-RNA 传感器，它已成为细胞死亡和炎症的关键调节因子。ZBP1 通过其 Zα 结构域结合 Z-DNA 和 Z-RNA，并通过其 RIP 同源相互作用基序（RHIM）与 RIPK3 和 RIPK1 结合来发出信号。在这里，我们表明，小鼠表达一种剪接方式不同的较短 ZBP1 异构体（ZBP1-S），它具有 Zα 结构域，但缺乏 RHIMs，并且作为全长蛋白（ZBP1-L）的内源性抑制剂发挥作用。只表达 ZBP1-S 的小鼠和细胞对 ZBP1 介导的细胞死亡和炎症具有抗性。相比之下，缺乏 ZBP1-S 的细胞比表达两种异构体的细胞显示出更高的 ZBP1-L 诱导的死亡。此外，缺失短异构体加速并加剧了由 ZBP1 介导的 RIPK1 缺陷角质形成细胞坏死引起的皮肤炎症，揭示了 ZBP1-S 的重要生理作用。在机制上，ZBP1-S 通过其 Zα 结构域与 Z-核酸结合，从而抑制 ZBP1-L 介导的细胞死亡。因此，ZBP1-S 作为一种内源性抑制剂，通过与全长 ZBP1-L 竞争结合 Z-核酸配体来精细调节 ZBP1 介导的细胞死亡和炎症。
