| First Author | Kesavardhana S | Year | 2020 |
| Journal | J Biol Chem | Volume | 295 |
| Issue | 24 | Pages | 8325-8330 |
| PubMed ID | 32350114 | Mgi Jnum | J:295921 |
| Mgi Id | MGI:6453154 | Doi | 10.1074/jbc.RA120.013752 |
| Citation | Kesavardhana S, et al. (2020) The Zalpha2 domain of ZBP1 is a molecular switch regulating influenza-induced PANoptosis and perinatal lethality during development. J Biol Chem 295(24):8325-8330 |
| abstractText | 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 Zalpha1 and Zalpha2 domains, which bind to nucleic acids in the Z-conformation. However, the specific role of these Zalpha domains in orchestrating ZBP1 activation and subsequent inflammation and cell death is not clear. Here we generated Zbp1 (DeltaZalpha2/DeltaZalpha2) mice that express ZBP1 lacking the Zalpha2 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 (Ripk1 (mRHIM/mRHIM)). Deletion of the Zalpha2 domain in ZBP1 abolished influenza A virus-induced PANoptosis and NLRP3 inflammasome activation. Furthermore, deletion of the Zalpha2 domain of ZBP1 was sufficient to rescue Ripk1 (mRHIM/mRHIM) mice from perinatal lethality caused by ZBP1-driven cell death and inflammation. Our findings identify the essential role of the Zalpha2 domain of ZBP1 in several physiological functions and establish a link between Z-RNA sensing via the Zalpha2 domain and promotion of influenza-induced PANoptosis and perinatal lethality. |
