Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Hartwell Center for Bioinformatics & Biotechnology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Cell Rep. 2021 Oct 19;37(3):109858. doi: 10.1016/j.celrep.2021.109858.
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. Adar1LysM 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.
细胞死亡提供宿主防御并维持体内平衡。含 Zα 的分子对于这些过程至关重要。Z-DNA 结合蛋白 1（ZBP1）激活炎症性细胞死亡，即 PANoptosis，而 RNA 腺苷脱氨酶 1（ADAR1）作为 RNA 编辑因子来维持体内平衡。在这里，我们鉴定并表征了 ADAR1 与 ZBP1 的相互作用，确定了其在细胞死亡调控和肿瘤发生中的作用。联合使用干扰素（IFNs）和核输出抑制剂（NEIs）可激活依赖于 ZBP1 的 PANoptosis。ADAR1 通过与 ZBP1 的 Zα2 结构域相互作用来抑制这种 PANoptosis，从而限制 ZBP1 和 RIPK3 的相互作用。Adar1LysM 小鼠不易发生结直肠癌和黑色素瘤的发展，但删除 ZBP1 的 Zα2 结构域会恢复这些小鼠的肿瘤发生。此外，用 IFN-γ 和 NEI KPT-330 治疗野生型小鼠可依赖于 ZBP1 来消退黑色素瘤。我们的研究结果表明，ADAR1 抑制 ZBP1 介导的 PANoptosis，从而促进肿瘤发生。阐明 ADAR1 和 ZBP1 在细胞死亡中的功能对于为癌症和其他疾病制定治疗策略具有重要意义。
