ArticleCell research2018
The BH3-only protein BAD mediates TNFα cytotoxicity despite concurrent activation of IKK and NF-κB in septic shock.
Article in Cell research, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 13 citations in OpenAlex.
- A portable nanobiosensor with machine learning: enabling multi-cytokines point-of-care testing and early identification of sepsis immunoparalysis.Journal of nanobiotechnology · 2026Article
- A Histone Deacetylase Activity Model for the Discovery and Validation of Sepsis Biomarkers.Endocrine, metabolic & immune disorders drug targets · 2026Article
- Identification and validation of autophagy-related genes in sepsis based on bioinformatics studies.Virology journal · 2025Article
- Genetic polymorphisms, biomarkers and signaling pathways associated with septic shock: from diagnosis to therapeutic targets.Burns & trauma · 2024Review
- Apoptotic cell death in disease-Current understanding of the NCCD 2023.Cell death and differentiation · 2023Review
- TSSK4 upregulation in alveolar epithelial type-II cells facilitates pulmonary fibrosis through HSP90-AKT signaling restriction and AT-II apoptosis.Cell death & disease · 2021Article
- BAD-mediated neuronal apoptosis and neuroinflammation contribute to Alzheimer's disease pathology.iScience · 2021Article
- Transcriptome Profiling of mInternational journal of molecular sciences · 2021Article
- BAD inactivation exacerbates rheumatoid arthritis pathology by promoting survival of sublining macrophages.eLife · 2020Article
- Stoichiometry and regulation network of Bcl-2 family complexes quantified by live-cell FRET assay.Cellular and molecular life sciences : CMLS · 2020Article
- Monocyte recruitment and activated inflammation are associated with thyroid carcinogenesis in a mouse model.American journal of cancer research · 2019Article
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Authors and funding
7 authors at 6 institutions in 2 countries.
Funding
Abstract
The inflammatory cytokine TNFα plays a crucial role in the pathology of many inflammatory and infectious diseases. However, the mechanism underlying TNFα cytotoxicity in these diseases is incompletely understood. Here we report that the pro-apoptotic BCL-2 family member BAD mediates TNFα cytotoxicity despite concurrent activation of IKK and NF-κB in vitro by inducing apoptosis in cultured cells and in vivo by eliciting tissue damage of multiple organs and contributing to mortality in septic shock. At high doses, TNFα significantly inactivates RhoA through activation of the Src-p190GAP pathway, resulting in massive actin stress fiber destabilization, followed by substantial BAD release from the cytoskeleton to the cytosol. Under this condition, activated IKK fails to phosphorylate all cytosolic BAD, allowing translocation of non-phosphorylated BAD to mitochondria to trigger apoptosis. Polymicrobial infection utilizes the same mechanism as high-dose TNFα to elicit apoptosis-associated tissue damage of multiple organs. Consequently, loss of Bad or elimination of BAD pro-apoptotic activity protects mice from tissue damage of multiple organs and reduces mortality rates. Our results support a model in which BAD mediates TNFα cytotoxicity despite concurrent activation of the IKK-NF-κB pathway in cultured mammalian cells and in septic shock.
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Registered trials
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