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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Oct 19, 2021 |
| Title |
ADAR1 restricts ZBP1–mediated immune response and PANoptosis to promote tumorigenesis |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Cell death provides host defense and maintains homeostasis. Zα-containing molecules are essential for these processes. ZBP1 activates inflammatory cell death, PANoptosis, while ADAR1 serves as an RNA editor to maintain homeostasis. Here, we identify and characterize ADAR1’s interaction with ZBP1, defining its role in cell death regulation and tumorigenesis. Combining IFNs and nuclear export inhibitors (NEIs) activates ZBP1–dependent PANoptosis. ADAR1 suppresses 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 wildtype 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 inform therapeutic strategies for cancer and other diseases.
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| Overall design |
We used microarrays to investigate global expression profiles in bone marrow derived macrophages from WT (Adar1fl/+LysMcre) and Adar1-deficient (Adar1fl/flLysMcre) mice
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| Contributor(s) |
Karki R, Sundaram B, Sharma BR, Lee S, Malireddi RK, Nguyen LN, Christgen S, Zheng M, Wang Y, Samir P, Neale G, Vogel P, Kanneganti T |
| Citation(s) |
34686350 |
| Submission date |
Sep 17, 2021 |
| Last update date |
Jan 18, 2022 |
| Contact name |
Geoffrey Neale |
| E-mail(s) |
geoffrey.neale@stjude.org
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| Organization name |
St Jude Childrens Research Hospital
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| Department |
Hartwell Center
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| Street address |
262 Danny Thomas Place
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| City |
Memphis |
| State/province |
TN |
| ZIP/Postal code |
38105 |
| Country |
USA |
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| Platforms (1) |
| GPL23038 |
[Clariom_S_Mouse] Affymetrix Clariom S Assay, Mouse (Includes Pico Assay) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA764065 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE184323_RAW.tar |
7.2 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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