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

Rajendra Karki, Balamurugan Sundaram, Bhesh Raj Sharma, Sang Joon Lee, R. K.Subbarao Malireddi, Lam Nhat Nguyen, Shelbi Christgen, Min Zheng, Yaqiu Wang, Parimal Samir, Geoffrey Neale, Peter Vogel, Thirumala Devi Kanneganti

Research output: Contribution to journalArticlepeer-review

162 Scopus citations

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.

Original languageEnglish (US)
Article number109858
JournalCell Reports
Volume37
Issue number3
DOIs
StatePublished - Oct 19 2021
Externally publishedYes

Keywords

  • ADAR1
  • IFN
  • PANoptosis
  • PANoptosome
  • ZBP1
  • apoptosis
  • inflammasome
  • necroptosis
  • pyroptosis
  • tumorigenesis

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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