ADAR1 restricts ZBP1-mediated immune response and PANoptosis to promote tumorigenesis

Area of Science:

• Immunology
• Molecular Biology
• Cancer Biology

Background:

• Cell death mechanisms are crucial for host defense and homeostasis.
• Z-DNA binding protein 1 (ZBP1) and adenosine deaminase acting on RNA 1 (ADAR1) are key regulators involved in cell death and homeostasis, respectively.
• The interplay between ZBP1 and ADAR1 in regulating cell death and its implications in tumorigenesis remain incompletely understood.

Purpose of the Study:

• To elucidate the interaction between ADAR1 and ZBP1.
• To define the role of ADAR1 in ZBP1-mediated cell death.
• To investigate the impact of the ADAR1-ZBP1 axis on tumorigenesis.

Main Methods:

• Biochemical assays to characterize ADAR1-ZBP1 interaction.
• In vivo studies using genetically modified mice (Adar1fl/flLysMcre).
• Pharmacological interventions with interferons (IFNs) and nuclear export inhibitors (NEIs) in mouse models.

Main Results:

• ADAR1 directly interacts with the Zα2 domain of ZBP1, inhibiting ZBP1-RIPK3 complex formation and suppressing ZBP1-dependent PANoptosis.
• Mice lacking ADAR1 are resistant to colorectal cancer and melanoma development.
• Deletion of the ZBP1 Zα2 domain in ADAR1-deficient mice restores tumorigenesis, and therapeutic inhibition of ZBP1 signaling in wild-type mice leads to melanoma regression.

Conclusions:

• ADAR1 acts as a suppressor of ZBP1-mediated PANoptosis, thereby promoting tumorigenesis.
• The findings highlight a critical role for the ADAR1-ZBP1 interaction in cancer development.
• Targeting the ADAR1-ZBP1 axis presents a potential therapeutic strategy for cancer treatment.