Proceedings of the National Academy of Sciences - PNAS, 2022-10, Vol.119 (41), p.e2207240119-e2207240119
2022
Details
- Autor(en) / Beteiligte
- Titel
- Caspase-8 and FADD prevent spontaneous ZBP1 expression and necroptosis
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2022-10, Vol.119 (41), p.e2207240119-e2207240119
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2022
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- The absence of Caspase-8 or its adapter, Fas-associated death domain (FADD), results in activation of receptor interacting protein kinase-3 (RIPK3)- and mixed-lineage kinase-like (MLKL)-dependent necroptosis in vivo. Here, we show that spontaneous activation of RIPK3, phosphorylation of MLKL, and necroptosis in Caspase-8- or FADD-deficient cells was dependent on the nucleic acid sensor, Z-DNA binding protein-1 (ZBP1). We genetically engineered a mouse model by a single insertion of FLAG tag onto the N terminus of endogenous MLKL ( ), creating an inactive form of MLKL that permits monitoring of phosphorylated MLKL without activating necroptotic cell death. mice were viable and displayed phosphorylated MLKL in a variety of tissues, together with dramatically increased expression of ZBP1 compared to mice. Studies in vitro revealed an increased expression of ZBP1 in cells lacking FADD or Caspase-8, which was suppressed by reconstitution of Caspase-8 or FADD. Ablation of ZBP1 in mice suppressed spontaneous MLKL phosphorylation in vivo. ZBP1 expression and downstream activation of RIPK3 and MLKL in cells lacking Caspase-8 or FADD relied on a positive feedback mechanism requiring the nucleic acid sensors cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), and TBK1 signaling pathways. Our study identifies a molecular mechanism whereby Caspase-8 and FADD suppress spontaneous necroptotic cell death.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.2207240119Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9565532
- Format
- –
- Schlagworte
- Ablation, Animals, Apoptosis, Apoptosis - physiology, Biological Sciences, Caspase 8 - genetics, Caspase 8 - metabolism, Caspase-8, Cell death, DNA structure, DNA-Binding Proteins - metabolism, FADD protein, Fas-Associated Death Domain Protein - genetics, Flags, Genetic engineering, Insertion, Interferon, Interferons - metabolism, Kinases, MAP kinase, Mice, Mortality, Necroptosis, Nucleic Acids, Nucleotidyltransferases - metabolism, Phosphorylation, Positive feedback, Protein kinase, Protein Kinases - genetics, Protein Kinases - metabolism, Proteins, Receptor-Interacting Protein Serine-Threonine Kinases - metabolism, RNA-Binding Proteins - genetics, RNA-Binding Proteins - metabolism, Stimulators