ZBP1 and TRIF trigger lethal necroptosis in mice lacking caspase-8 and TNFR1

• Published in: Cell death and differentiation 2024-05, Vol.31 (5), p.672-682
• Main Authors: Solon, Margaret, Ge, Nianfeng, Hambro, Shannon, Haller, Susan, Jiang, Jian, Baca, Miriam, Preston, Jessica, Maltzman, Allie, Wickliffe, Katherine E., Liang, Yuxin, Reja, Rohit, Nickles, Dorothee, Newton, Kim, Webster, Joshua D.
• Format: Article
• Language: English
• Subjects: 13/1; 13/31; 38/71; 38/91; 631/250/1932; 631/250/1933; 64/60; 82/51; Adaptor proteins; Adaptor Proteins, Vesicular Transport - genetics; Adaptor Proteins, Vesicular Transport - metabolism; Animals; Antibodies; Apoptosis; Biochemistry; Biomedical and Life Sciences; Caspase 8 - genetics; Caspase 8 - metabolism; Caspase-8; Cell Biology; Cell Cycle Analysis; Cell death; Death receptors; Embryos; Endothelial cells; Granulocytes; Hybridization; Immunohistochemistry; Kinases; Labeling; Lethality; Life Sciences; Lymphatic system; Mice; Mice, Inbred C57BL; Mice, Knockout; Morbidity; Necroptosis; Oligomerization; Oncology; Protein Kinases - genetics; Protein Kinases - metabolism; Receptor-Interacting Protein Serine-Threonine Kinases - genetics; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Receptors, Tumor Necrosis Factor, Type I - genetics; Receptors, Tumor Necrosis Factor, Type I - metabolism; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Small intestine; Stem Cells; TLR3 protein; TLR4 protein; Toll-like receptors; Tumor necrosis factor receptors; Tumor necrosis factor-TNF; Z-form
• ISSN: 1350-9047; 1476-5403; 1476-5403
• DOI: 10.1038/s41418-024-01286-6

Necroptosis is a lytic form of cell death that is mediated by the kinase RIPK3 and the pseudokinase MLKL when caspase-8 is inhibited downstream of death receptors, toll-like receptor 3 (TLR3), TLR4, and the intracellular Z-form nucleic acid sensor ZBP1. Oligomerization and activation of RIPK3 is driven by interactions with the kinase RIPK1, the TLR adaptor TRIF, or ZBP1. In this study, we use immunohistochemistry (IHC) and in situ hybridization (ISH) assays to generate a tissue atlas characterizing RIPK1, RIPK3, Mlkl , and ZBP1 expression in mouse tissues. RIPK1, RIPK3, and Mlkl were co-expressed in most immune cell populations, endothelial cells, and many barrier epithelia. ZBP1 was expressed in many immune populations, but had more variable expression in epithelia compared to RIPK1, RIPK3, and Mlkl . Intriguingly, expression of ZBP1 was elevated in Casp8 −/− Tnfr1 −/− embryos prior to their succumbing to aberrant necroptosis around embryonic day 15 (E15). ZBP1 contributed to this embryonic lethality because rare Casp8 −/− Tnfr1 −/− Zbp1 −/− mice survived until after birth. Necroptosis mediated by TRIF contributed to the demise of Casp8 −/− Tnfr1 −/− Zbp1 −/− pups in the perinatal period. Of note, Casp8 −/− Tnfr1 −/− Trif −/− Zbp1 −/− mice exhibited autoinflammation and morbidity, typically within 5–7 weeks of being born, which is not seen in Casp8 −/− Ripk1 −/− Trif −/− Zbp1 −/− , Casp8 −/− Ripk3 −/− , or Casp8 −/− Mlkl −/− mice. Therefore, after birth, loss of caspase-8 probably unleashes RIPK1-dependent necroptosis driven by death receptors other than TNFR1.