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.

中文翻译：

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较短的剪接亚型拮抗 ZBP1 以调节细胞死亡和炎症反应。


Z-DNA 结合蛋白 1 （ZBP1） 是 Z-DNA 和 Z-RNA 的干扰素诱导传感器，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 同型相互作用基序 （RHIM） 结合 RIPK3 和 RIPK1 进行信号传递。在这里，我们表明小鼠表达一种可变剪接的较短 ZBP1 亚型 （ZBP1-S），它包含 Zα 结构域但缺乏 RHIM，并充当全长蛋白 （ZBP1-L） 的内源性抑制剂。仅表达 ZBP1-S 的小鼠和细胞对 ZBP1 介导的细胞死亡和炎症具有抵抗力。相比之下，与表达两种亚型的细胞相比，缺乏 ZBP1-S 的细胞显示 ZBP1-L 诱导的死亡增加。此外，短亚型的缺失加速并加剧了 ZBP1 介导的 RIPK1 缺陷角质形成细胞坏死性凋亡诱导的皮肤炎症，揭示了 ZBP1-S 的重要生理作用。从机制上讲，ZBP1-S 通过其 Zα 结构域与 Z 核酸结合来抑制 ZBP1-L 介导的细胞死亡。因此，ZBP1-S 作为一种内源性抑制剂，与全长 ZBP1-L 竞争结合 Z 核酸配体以微调 ZBP1 介导的细胞死亡和炎症。