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. 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.
Highlights
Nucleic acids, double-stranded RNA from pathogens, are sensed by cytosolic RNA sensors to produce type I interferons (IFNs), which provide host defense against invading microbes (Yoneyama et al, 2004)
Using adenosine deaminase acting on RNA 1 (ADAR1)-deficient macrophages, we found that ADAR1 competes with RIPK3 for binding to Z-DNA binding protein 1 (ZBP1) to inhibit cell death; when ADAR1 is lost or sequestered in the nucleus by nuclear export inhibitors (NEIs) treatment, ZBP1 can function in the cytoplasm without hindrance to drive inflammatory cell death, PANoptosis
To determine the contribution of other critical cell death molecules to the inflammatory cell death induced by IFNs and NEIs, we examined the role of the pyroptosis initiators (CASP1 and CASP11), pyroptosis executioners (GSDMD and GSDME), apoptosis executioners (CASP3 and CASP7), and necroptosis executioner (MLKL) in the cell death
Summary
Double-stranded RNA (dsRNA) from pathogens, are sensed by cytosolic RNA sensors to produce type I interferons (IFNs), which provide host defense against invading microbes (Yoneyama et al, 2004). The sensors can recognize some endogenous RNAs, such as short interspersed nuclear elements and endogenous retroelements (EREs), leading to sustained and profound IFN production in the absence of infection (Ahmad et al, 2018; Jiao et al, 2020; Kim et al, 2004; Neeman et al, 2006; Wang et al, 2020) To avoid this pathological overactivation of the immune system, host RNAs undergo a post-transcriptional RNA base modification catalyzed by adenosine deaminase acting on RNA 1 (ADAR1), preventing the sensing of endogenous dsRNA (Nishikura, 2010). The underlying mechanisms remain unclear, recent studies have suggested an association between ADAR1 and tumorigenesis (Fumagalli et al, 2015; Han et al, 2015; Liu et al, 2019; Paz-Yaacov et al, 2015; Tassinari et al, 2021)
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