Zbp1, also known as Z-DNA-binding protein 1, DAI or DLM-1, is a critical innate immune sensor. It harbors nucleic acid-binding domains for left-handed helix (Z-form) and receptor-interacting protein homotypic interaction motif (RHIM) domains for protein homotypic interactions [3]. Zbp1 is involved in sensing viral RNA products and endogenous nucleic acid ligands, regulating cell death (such as pyroptosis, apoptosis, necroptosis, and PANoptosis), inflammasome activation, and pro-inflammatory responses [1,3,4,6,7,8]. Genetic models, like KO mouse models, are valuable for studying Zbp1's functions.

In Influenza A virus infection, Zbp1 senses the Z-RNA produced, initiating RIPK3-driven cell death. Zbp1-deficient mice show reduced nuclear disruption of lung epithelia, decreased neutrophil recruitment into infected lungs, and increased survival following a lethal dose of IAV, indicating Zbp1's role in the pathogenic consequences of severe influenza [2]. In addition, in mice with specific genetic deficiencies related to RIPK1 or FADD, Zα-dependent sensing of endogenous ligands by Zbp1 induces perinatal lethality, skin inflammation, and colitis, suggesting Zbp1's role in RIPK3-dependent necroptosis and inflammation in chronic inflammatory conditions [7]. Mice lacking Zbp1 are protected from Doxorubicin-induced cardiotoxicity as Zbp1 cooperates with cGAS to sustain type I interferon (IFN-I) responses to mitochondrial genome instability [5]. Adar1fl/flLysMcre mice (with a certain genetic modification) are resistant to the development of colorectal cancer and melanoma, but deletion of the ZBP1 Zα2 domain restores tumorigenesis in these mice, showing Zbp1's role in tumorigenesis regulation [4].

In conclusion, Zbp1 is a key innate immune sensor regulating cell death, inflammation, and immune responses. Studies using KO/CKO mouse models have revealed its significance in diseases such as influenza-related pathology, cardiotoxicity, and tumorigenesis. Understanding Zbp1's functions provides potential therapeutic strategies 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. 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/

4. 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/

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. Chen, Xin-Yu, Dai, Ying-Hong, Wan, Xin-Xing, Zhang, Qi, Xiong, Kun. 2022. ZBP1-Mediated Necroptosis: Mechanisms and Therapeutic Implications. In Molecules (Basel, Switzerland), 28, . doi:10.3390/molecules28010052. https://pubmed.ncbi.nlm.nih.gov/36615244/