@article{1dd9df4f20564459bdc1d70f7936f6bd,
title = "ADAR1 restricts ZBP1-mediated immune response and PANoptosis to promote tumorigenesis",
abstract = "Cell death provides host defense and maintains homeostasis. Zα-containing molecules are essential for these processes. Z-DNA binding protein 1 (ZBP1) activates inflammatory cell death, PANoptosis, whereas adenosine deaminase acting on RNA 1 (ADAR1) serves as an RNA editor to maintain homeostasis. Here, we identify and characterize ADAR1{\textquoteright}s interaction with ZBP1, defining its role in cell death regulation and tumorigenesis. Combining interferons (IFNs) and nuclear export inhibitors (NEIs) activates ZBP1-dependent PANoptosis. ADAR1 suppresses this PANoptosis by interacting with the Zα2 domain of ZBP1 to limit ZBP1 and RIPK3 interactions. Adar1fl/flLysMcre mice are resistant to development of colorectal cancer and melanoma, but deletion of the ZBP1 Zα2 domain restores tumorigenesis in these mice. In addition, treating wild-type mice with IFN-γ and the NEI KPT-330 regresses melanoma in a ZBP1-dependent manner. Our findings suggest that ADAR1 suppresses ZBP1-mediated PANoptosis, promoting tumorigenesis. Defining the functions of ADAR1 and ZBP1 in cell death is fundamental to informing therapeutic strategies for cancer and other diseases.",
keywords = "ADAR1, IFN, PANoptosis, PANoptosome, ZBP1, apoptosis, inflammasome, necroptosis, pyroptosis, tumorigenesis",
author = "Rajendra Karki and Balamurugan Sundaram and Sharma, {Bhesh Raj} and Lee, {Sang Joon} and Malireddi, {R. K.Subbarao} and Nguyen, {Lam Nhat} and Shelbi Christgen and Min Zheng and Yaqiu Wang and Parimal Samir and Geoffrey Neale and Peter Vogel and Kanneganti, {Thirumala Devi}",
note = "Funding Information: We thank all the members of the Kanneganti laboratory for their comments and suggestions during the development of this manuscript. We also thank R. Tweedell, PhD, and J. Gullett, PhD, for scientific editing and writing support. Work from our laboratory is supported by the National Institutes of Health (AI101935, AI124346, AI160179, AR056296, and CA253095 to T.-D.K.) and the American Lebanese Syrian Associated Charities (to T.-D.K.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank V.M. Dixit and N. Kayagaki (Genentech) for the Casp11−/− mutant mouse strain, and we thank Dr. Michael Gale for providing Mavs−/− mutant mice. R.K. and T.-D.K. conceptualized the study; R.K. designed the methodology; R.K. B.S. B.R.S. S.L. R.K.S.M. L.N.N. M.Z. Y.W. and S.C. performed the experiments; P.S. and G.N. conducted the gene expression and publicly available dataset analysis; P.V. conducted the pathology analysis; R.K. and T.-D.K. wrote the manuscript with input from all the authors; T.-D.K. acquired the funding and provided overall supervision. St. Jude Children's Research hospital filed a provisional patent application on the IFN and NEI treatment strategy described in this study, listing R.K. and T.-D.K. as inventors (serial no. 63/196,986). Funding Information: We thank all the members of the Kanneganti laboratory for their comments and suggestions during the development of this manuscript. We also thank R. Tweedell, PhD, and J. Gullett, PhD, for scientific editing and writing support. Work from our laboratory is supported by the National Institutes of Health ( AI101935 , AI124346 , AI160179 , AR056296 , and CA253095 to T.-D.K.) and the American Lebanese Syrian Associated Charities (to T.-D.K.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank V.M. Dixit and N. Kayagaki (Genentech) for the Casp11 −/− mutant mouse strain, and we thank Dr. Michael Gale for providing Mavs −/− mutant mice. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = oct,
day = "19",
doi = "10.1016/j.celrep.2021.109858",
language = "English (US)",
volume = "37",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "3",
}