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

Cell Rep. 2021 Oct 19;37(3):109858. doi: 10.1016/j.celrep.2021.109858.

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.

Keywords: ADAR1; IFN; PANoptosis; PANoptosome; ZBP1; apoptosis; inflammasome; necroptosis; pyroptosis; tumorigenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Deaminase / genetics
  • Adenosine Deaminase / metabolism*
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Cell Death
  • Cell Transformation, Neoplastic / immunology
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / enzymology*
  • Colorectal Neoplasms / immunology
  • Colorectal Neoplasms / pathology
  • Female
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Humans
  • Hydrazines / pharmacology
  • Interferon-gamma / pharmacology
  • Male
  • Melanoma, Experimental / drug therapy
  • Melanoma, Experimental / enzymology*
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Necroptosis
  • Pyroptosis
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Signal Transduction
  • Skin Neoplasms / drug therapy
  • Skin Neoplasms / enzymology*
  • Skin Neoplasms / immunology
  • Skin Neoplasms / pathology
  • Triazoles / pharmacology

Substances

  • Hydrazines
  • RNA-Binding Proteins
  • Triazoles
  • Zbp1 protein, mouse
  • selinexor
  • Interferon-gamma
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk3 protein, mouse
  • ADAR1 protein, mouse
  • Adenosine Deaminase