1. Antioxidant and food additive BHA prevents TNF cytotoxicity by acting as a direct RIPK1 inhibitor
- Author
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Mathieu J.M. Bertrand, Jon Huyghe, Tom Delanghe, Dario Priem, Alexei Degterev, Sze Men Choi, Yves Dondelinger, Samya Van Coillie, Barbara Gilbert, Gregory D. Cuny, Seungheon Lee, and Peter Vandenabeele more...
- Subjects
0301 basic medicine ,Cancer Research ,Antioxidant ,medicine.medical_treatment ,NF-KAPPA-B ,Butylated Hydroxyanisole ,Apoptosis ,Pharmacology ,Antioxidants ,Mice ,0302 clinical medicine ,NEMO ,Medicine and Health Sciences ,DOMAIN-LIKE ,PHOSPHORYLATION ,Cytotoxicity ,TUMOR-NECROSIS-FACTOR ,chemistry.chemical_classification ,Chemistry ,Intracellular Signaling Peptides and Proteins ,Systemic Inflammatory Response Syndrome ,APOPTOSIS ,Molecular Docking Simulation ,Receptor-Interacting Protein Serine-Threonine Kinases ,030220 oncology & carcinogenesis ,Necroptosis ,Female ,Tumor necrosis factor alpha ,HT29 Cells ,Protein Binding ,Programmed cell death ,Immunology ,Mice, Transgenic ,Kinases ,Article ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,RIPK1 ,INFLAMMATION ,Target identification ,Cell death and immune response ,MIXED LINEAGE KINASE ,medicine ,Animals ,Humans ,NECROPTOSIS ,Protein Kinase Inhibitors ,Reactive oxygen species ,QH573-671 ,Tumor Necrosis Factor-alpha ,Biology and Life Sciences ,Cell Biology ,Fibroblasts ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,CELL-DEATH ,Food Additives ,INDUCED ,Cytology - Abstract
Butylate hydroxyanisole (BHA) is a synthetic phenol that is widely utilized as a preservative by the food and cosmetic industries. The antioxidant properties of BHA are also frequently used by scientists to claim the implication of reactive oxygen species (ROS) in various cellular processes, including cell death. We report on the surprising finding that BHA functions as a direct inhibitor of RIPK1, a major signaling hub downstream of several immune receptors. Our in silico analysis predicts binding of 3-BHA, but not 2-BHA, to RIPK1 in an inactive DLG-out/Glu-out conformation, similar to the binding of the type III inhibitor Nec-1s to RIPK1. This predicted superior inhibitory capacity of 3-BHA over 2-BHA was confirmed in cells and using in vitro kinase assays. We demonstrate that the reported protective effect of BHA against tumor necrosis factor (TNF)-induced necroptotic death does not originate from ROS scavenging but instead from direct RIPK1 enzymatic inhibition, a finding that most probably extends to other reported effects of BHA. Accordingly, we show that BHA not only protects cells against RIPK1-mediated necroptosis but also against RIPK1 kinase-dependent apoptosis. We found that BHA treatment completely inhibits basal and induced RIPK1 enzymatic activity in cells, monitored at the level of TNFR1 complex I under apoptotic conditions or in the cytosol under necroptosis. Finally, we show that oral administration of BHA protects mice from RIPK1 kinase-dependent lethality caused by TNF injection, a model of systemic inflammatory response syndrome. In conclusion, our results demonstrate that BHA can no longer be used as a strict antioxidant and that new functions of RIPK1 may emerge from previously reported effects of BHA. more...
- Published
- 2021
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