Receptor Interacting Protein Kinase-3 Determines Cellular Necrotic Response to TNF-α
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Smac mimetics induce apoptosis synergistically with TNF-alpha by triggering the formation of a caspase-8-activating complex containing receptor interacting protein kinase-1 (RIPK1). Caspase inhibitors block this form of apoptosis in many types of cells. However, in several other cell lines, caspase inhibitors switch the apoptotic response to necrosis. A genome wide siRNA screen revealed another member of the RIP kinase family, RIP3, to be required for necrosis. The expression of RIP3 in different cell lines correlates with their responsiveness to necrosis induction. The kinase activity of RIP3 is essential for necrosis execution. Upon induction of necrosis, RIP3 is recruited to RIPK1 to form a necrosis-inducing complex. Embryonic fibroblasts from RIP3 knockout mice are resistant to necrosis and RIP3 knockout animals are devoid of inflammation inflicted tissue damage in an acute pancreatitis model. These data indicate RIP3 as the determinant for cellular necrosis in response to TNF-alpha family of death-inducing cytokines.
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Excess TNF-α may induce apoptosis and necrosis of infected macrophages via stimulation of receptor-interacting serine-threonine kinases 1 and 3 and excessive radical formation.
“However, excess TNF-α may have the opposite effect by inducing apoptosis and necrosis of infected macrophages via stimulation of receptor-interacting serine-threonine kinases 1 and 3 (RIP1 and RIP3) and excessive radical formation (64–66).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [64]
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- Authors
- He, S., Wang, L., Miao, L., Wang, T., Du, F., Zhao, L., & Wang, X.
- Affiliations
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Howard Hughes Medical Institute (US)
- National Institute of Biological Sciences, Beijing (CN)
- Corresponding author
- Wang, Xiaodong
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2009-06
- Volume
- 137
- Issue
- 6
- Pages
- 1100-1111
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2052605153
- Cited by
- 2,214
- References
- 35
- Citations by year
- 2026: 82 · 2025: 118 · 2024: 114 · 2023: 124 · 2022: 158 · 2021: 168 · 2020: 147 · 2019: 136 · 2018: 143 · 2017: 147 · 2016: 171 · 2015: 155 · 2014: 179 · 2013: 101 · 2012: 106
- FWCI
- 36.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (submittedVersion)
- Funders
- National Institutes of Health (5p01ca095471-10)
- National Cancer Institute (P01 CA95471)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Social Sciences › Anthropology › Death, Funerary Practices, and Mourning
- Keywords
- RIPK3, receptor-interacting protein kinase, necrosis, TNF-α, RIPK1, IAP antagonists, caspase-8, kinase activity, acute pancreatitis, inflammation, siRNA screen
- MeSH terms
- Animals, Ceruletide, Humans, Mutation, Necrosis, Pancreatitis, Tumor Necrosis Factor-alpha, Protein Structure, Tertiary, RNA, Small Interfering, Cell Line, Tumor, Mice, Receptor-Interacting Protein Serine-Threonine Kinases
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