Cited by 1,931Cell death mechanisms and regulationNF-κB Signaling PathwaysDeath, Funerary Practices, and Mourning

RIP3, an Energy Metabolism Regulator That Switches TNF-Induced Cell Death from Apoptosis to Necrosis

Zhang, Duan-Wu, Shao, Jing, Lin, Juan, Zhang, Na, Lu, Bao-Ju, Lin, Sheng-Cai, Dong, Meng-Qiu, Han, Jiahuai·2009·Science

Abstract

Necrosis can be induced by stimulating death receptors with tumor necrosis factor (TNF) or other agonists; however, the underlying mechanism differentiating necrosis from apoptosis is largely unknown. We identified the protein kinase receptor-interacting protein 3 (RIP3) as a molecular switch between TNF-induced apoptosis and necrosis in NIH 3T3 cells and found that RIP3 was required for necrosis in other cells. RIP3 did not affect RIP1-mediated apoptosis but was required for RIP1-mediated necrosis and the enhancement of necrosis by the caspase inhibitor zVAD. By activating key enzymes of metabolic pathways, RIP3 regulates TNF-induced reactive oxygen species production, which partially accounts for RIP3's ability to promote necrosis. Our data suggest that modulation of energy metabolism in response to death stimuli has an important role in the choice between apoptosis and necrosis.

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Crossref · 10.1126/science.1172308

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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 [65]

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Authors
Zhang, D.-W., Shao, J., Lin, J., Zhang, N., Lu, B.-J., Lin, S.-C., Dong, M.-Q., & Han, J.
Affiliations
  • Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
  • Xiamen University (CN)
  • National Institute of Biological Sciences, Beijing (CN)
Corresponding author
Han, Jiahuai
Venue
Science
Published
2009-07-17
Volume
325
Issue
5938
Pages
332-336
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
OpenAlex
W2060204808
Cited by
1,931
References
22
Citations by year
2026: 52 · 2025: 106 · 2024: 95 · 2023: 115 · 2022: 142 · 2021: 135 · 2020: 109 · 2019: 105 · 2018: 124 · 2017: 131 · 2016: 140 · 2015: 128 · 2014: 174 · 2013: 105 · 2012: 107
FWCI
36.27
Type
journal article
Language
en
Open access
closed
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
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, necroptosis, TNF-induced cell death, apoptosis, energy metabolism, RIPK1, reactive oxygen species, death receptor signaling, programmed cell death
MeSH terms
Amino Acid Chloromethyl Ketones, Animals, Cell Line, Energy Metabolism, Glutamate Dehydrogenase, Glutamate-Ammonia Ligase, Necrosis, Tumor Necrosis Factor-alpha, Apoptosis, Reactive Oxygen Species, Glycogen Phosphorylase, RNA Interference, NIH 3T3 Cells, Mice, Receptor-Interacting Protein Serine-Threonine Kinases

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