Abstract
Z-DNA-binding protein 1 (ZBP1) is an innate immune sensor of nucleic acids that regulates host defense responses and development. ZBP1 activation triggers inflammation and pyroptosis, necroptosis, and apoptosis (PANoptosis) by activating receptor-interacting Ser/Thr kinase 3 (RIPK3), caspase-8, and the NLRP3 inflammasome. ZBP1 is unique among innate immune sensors because of its N-terminal Zα1 and Zα2 domains, which bind to nucleic acids in the Z-conformation. However, the specific role of these Zα domains in orchestrating ZBP1 activation and subsequent inflammation and cell death is not clear. Here we generated Zbp1ΔZα2/ΔZα2 mice that express ZBP1 lacking the Zα2 domain and demonstrate that this domain is critical for influenza A virus-induced PANoptosis and underlies perinatal lethality in mice in which the RIP homotypic interaction motif domain of RIPK1 has been mutated (Ripk1mRHIM/mRHIM). Deletion of the Zα2 domain in ZBP1 abolished influenza A virus-induced PANoptosis and NLRP3 inflammasome activation. Furthermore, deletion of the Zα2 domain of ZBP1 was sufficient to rescue Ripk1mRHIM/mRHIM mice from perinatal lethality caused by ZBP1-driven cell death and inflammation. Our findings identify the essential role of the Zα2 domain of ZBP1 in several physiological functions and establish a link between Z-RNA sensing via the Zα2 domain and promotion of influenza-induced PANoptosis and perinatal lethality.
Highlights
Z-DNA-binding protein 1 (ZBP1) is an innate immune sensor of nucleic acids that regulates host defense responses and development
influenza A virus (IAV) infection did not induce cell death in Ripk1mRHIM/mRHIMZbp1⌬Z␣2/⌬Z␣2 or Ripk1mRHIM/mRHIMZbp1Ϫ/Ϫ bone marrow– derived macrophage (BMDM) (Fig. S2D). These results suggest that deletion of the Z␣2 domain of ZBP1 prevents cell death and perinatal lethality in Ripk1mRHIM/mRHIM mice and facilitates normal immune cell development in these mice, with a mild increase in circulating neutrophils
Several recent studies unraveled an important role of ZBP1 in regulating cell death and inflammation and uncovered its role as an innate immune sensor
Summary
Z-DNA-binding protein 1 (ZBP1) is an innate immune sensor of nucleic acids that regulates host defense responses and development. We identify the critical role of the Z␣2 domain of ZBP1 in regulating IAV-induced NLRP3 inflammasome activation, cell death, and perinatal lethality during mouse development. We generated ZBP1 mutant mice with deletion of the Z␣2 domain, which contains critical residues essential for Z-nucleic acid recognition, in the C57BL/6 background using CRISPR/Cas9 technology (hereafter referred to as Zbp1⌬Z␣2/⌬Z␣2 mice) (Fig. 1A and Table S1).
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