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

Abstract

Cell death provides host defense and maintains homeostasis. Za-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 Za2 domain of ZBP1 to limit ZBP1 and RIPK3 interactions. Adar1 fl/fl LysM cre mice are resistant to development of colorectal cancer and melanoma, but deletion of the ZBP1 Za2 domain restores tumorigenesis in these mice. In addition, treating wild-type mice with IFN-g 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.

The Transcription Factor IRF9 Promotes Colorectal Cancer via Modulating the IL-6/STAT3 Signaling Axis

“…The IFN signaling pathway is known to be important in this process; for example, IRF1 acts as a tumor suppressor in a mouse model of CRC and in human cancer cells by promoting PANoptosis [ 21 , 22 ]. PANoptosis is an innate immune inflammatory programmed cell death pathway dependent on PANoptosomes, caspase(s)-containing complexes with or without inflammasome components and RHIM-containing proteins [ 15 , 21 , 22 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ]. Given that Irf9 −/− mice develop fewer CRC tumors, we hypothesized that cell death pathways may be modulated in the colon of these mice.…”

Integrated stress response restricts macrophage necroptosis

“…More recently, the extensive crosstalk between cell death pathways has led to the concept of PANoptosis, which is defined as an inflammatory programmed cell death pathway regulated by the PANoptosome complex with key features of pyroptosis, apoptosis, and/or necroptosis that cannot be accounted for by any of these pathways alone. The PANoptosome provides a molecular scaffold for contemporaneous engagement of key molecules from pyroptosis, apoptosis, and necroptosis (Lamkanfi et al, 2008;Malireddi et al, 2010Malireddi et al, , 2018Malireddi et al, , 2019Malireddi et al, , 2020aMalireddi et al, , 2020bGurung et al, 2014Gurung et al, , 2016Lukens et al, 2014;Kuriakose et al, 2016;Banoth et al, 2020;Christgen et al, 2020;Karki et al, 2020aKarki et al, , 2020bKarki et al, , 2021Kesavardhana et al, 2020b;Lee et al, 2021). Given the inflammatory consequences of cell death, cells possess multiple negative regulatory pathways that restrict excessive inflammation.…”

Programmed Cell Death Tunes Tumor Immunity

“…For instance, IFNγ, together with TNFα, could induce PANoptosis in diverse cancer cell lines and reduced tumor size in an immunodeficient mice model ( 150 ). Moreover, blocking the interaction of ZBP1, (the key mediator in PANoptosis) with RIPK3 or deletion of key PANoptosis regulatory element IRF1 (Interferon regulatory factor 1) suppressed PANoptosis and promoted tumorigenesis in mice studies ( 151 , 152 ). Therefore, harnessing the potent immunogenicity of PANoptosis might strengthen anti-tumor immunity in TME.…”