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'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. Adar1^fl/flLysM^cre mice are resistant to development of colorectal cancer and melanoma, but deletion of the ZBP1 Zα2 domain restores tum

SUBMITTER: Karki R 

PROVIDER: S-EPMC8853634 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature