Zbp1, also known as Z-DNA binding protein 1, DAI or DLM-1, is a crucial innate immune sensor that binds to Z-form nucleic acids (Z-DNA and Z-RNA) via its Zα domains and contains receptor-interacting protein homotypic interaction motif (RHIM) domains for protein-protein interactions [4,7]. It plays a vital role in regulating cell death, inflammasome activation, and pro-inflammatory responses, which are associated with pathways like pyroptosis, apoptosis, necroptosis (collectively known as PANoptosis), type I interferon signaling, and the unfolded protein response. These functions are of great biological importance in host defense against viral infections, maintaining homeostasis, and tumorigenesis [1,3,4,6,8]. Genetic models, such as gene knockout (KO) and conditional knockout (CKO) mouse models, are valuable for studying Zbp1.

In Ripk1mR/mR mice expressing RIPK1 with mutated RHIM, Zα-dependent sensing of endogenous ligands by Zbp1 leads to perinatal lethality, indicating its role in regulating necroptosis and inflammation under specific genetic conditions [7]. Adar1fl/flLysMcre mice lacking ADAR1, which interacts with Zbp1, are resistant to colorectal cancer and melanoma development, but deletion of the ZBP1 Zα2 domain restores tumorigenesis, suggesting Zbp1's role in tumorigenesis regulation [3]. In addition, MLKL-deficient mice show reduced nuclear disruption of lung epithelia, decreased neutrophil recruitment, and increased survival after a lethal dose of influenza A virus, as Zbp1-mediated necroptosis is affected, highlighting Zbp1's role in influenza-related pathogenesis [2]. Mice lacking Zbp1 or IFN-I signaling are protected from Doxorubicin-induced cardiotoxicity, revealing Zbp1's contribution to this form of cardiotoxicity through its role in mitochondrial DNA sensing and IFN-I signaling [5].

In conclusion, Zbp1 is a key regulator in multiple biological processes. Through KO/CKO mouse models, its functions in viral infection-related cell death, tumorigenesis, and cardiotoxicity have been well-demonstrated. These model-based studies provide insights into Zbp1's essential biological functions, which may offer potential therapeutic targets for infectious, inflammatory, and cancer diseases.

References:

1. Zheng, Min, Kanneganti, Thirumala-Devi. 2020. The regulation of the ZBP1-NLRP3 inflammasome and its implications in pyroptosis, apoptosis, and necroptosis (PANoptosis). In Immunological reviews, 297, 26-38. doi:10.1111/imr.12909. https://pubmed.ncbi.nlm.nih.gov/32729116/

2. Zhang, Ting, Yin, Chaoran, Boyd, David F, Green, Douglas R, Balachandran, Siddharth. . Influenza Virus Z-RNAs Induce ZBP1-Mediated Necroptosis. In Cell, 180, 1115-1129.e13. doi:10.1016/j.cell.2020.02.050. https://pubmed.ncbi.nlm.nih.gov/32200799/

3. Karki, Rajendra, Sundaram, Balamurugan, Sharma, Bhesh Raj, Vogel, Peter, Kanneganti, Thirumala-Devi. . ADAR1 restricts ZBP1-mediated immune response and PANoptosis to promote tumorigenesis. In Cell reports, 37, 109858. doi:10.1016/j.celrep.2021.109858. https://pubmed.ncbi.nlm.nih.gov/34686350/

4. Kuriakose, Teneema, Kanneganti, Thirumala-Devi. 2017. ZBP1: Innate Sensor Regulating Cell Death and Inflammation. In Trends in immunology, 39, 123-134. doi:10.1016/j.it.2017.11.002. https://pubmed.ncbi.nlm.nih.gov/29236673/

5. Lei, Yuanjiu, VanPortfliet, Jordyn J, Chen, Yi-Fan, Li, Pingwei, West, A Phillip. 2023. Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity. In Cell, 186, 3013-3032.e22. doi:10.1016/j.cell.2023.05.039. https://pubmed.ncbi.nlm.nih.gov/37352855/

6. Karki, Rajendra, Kanneganti, Thirumala-Devi. 2023. ADAR1 and ZBP1 in innate immunity, cell death, and disease. In Trends in immunology, 44, 201-216. doi:10.1016/j.it.2023.01.001. https://pubmed.ncbi.nlm.nih.gov/36710220/

7. Jiao, Huipeng, Wachsmuth, Laurens, Kumari, Snehlata, Kaiser, William J, Pasparakis, Manolis. 2020. Z-nucleic-acid sensing triggers ZBP1-dependent necroptosis and inflammation. In Nature, 580, 391-395. doi:10.1038/s41586-020-2129-8. https://pubmed.ncbi.nlm.nih.gov/32296175/

8. Gomes, Marco Túlio R, Guimarães, Erika S, Oliveira, Sergio C. 2025. ZBP1 senses Brucella abortus DNA triggering type I interferon signaling pathway and unfolded protein response activation. In Frontiers in immunology, 15, 1511949. doi:10.3389/fimmu.2024.1511949. https://pubmed.ncbi.nlm.nih.gov/39850894/