Necroptosis in health and diseases
Open accessAbstract
Necroptosis is a form of regulated necrosis that can be activated by ligands of death receptors and stimuli that induce the expression of death receptor ligands under apoptotic deficient conditions. Activation of necroptosis by ligands of death receptors requires the kinase activity of RIP1, which mediates the activation of RIP3 and MLKL, two critical downstream mediators of necroptosis. Blocking the kinase activity of RIP1, a key druggable target in the necroptosis pathway, by necrostatins inhibits the activation of necroptosis and allows cell survival and proliferation in the presence of death receptor ligands. The activation of necroptosis is modulated by different forms of ubiquitination, including K63, linear and K48 ubiquitination, as well as phosphorylation of RIP1, RIP3 and MLKL. Necroptosis is suppressed by caspase-8/FADD-mediated apoptosis. Deficiency in caspase-8 and FADD leads to embryonic lethality, tissue degeneration and inflammation which can be suppressed by inhibition of RIP1 kinase and RIP3. On the other hand, the lack of RIP3 kinase activity leads to early embryonic lethality which can be suppressed by the loss of caspase-8, suggesting that although the kinase activity of RIP3 is involved in mediating necroptosis, the basal activity of RIP3 kinase may be required for suppressing caspase-8 mediated apoptosis. Necroptosis as well as RIP1- and RIP3-mediated inflammatory response have been implicated in mediating multiple human diseases including TNF-mediated hypothermia and systemic inflammation, ischemic reperfusion injury, neurodegeneration, Gaucher's disease, progressive atherosclerotic lesions, etc. Targeting RIP1 kinase may provide therapeutic benefits for the treatment of human diseases characterized by necrosis and inflammation.
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Erastin-induced death still occurs when RIPK1/RIPK3 are knocked down or RIPK1 is inhibited, so it does not require known necroptosis components.
“Although non-apoptotic, erastin-induced cell death proceeds normally upon knockdown of RIPK1/RIPK3, or pharmacological inhibition of RIPK1 [10, 15, our unpublished data], known components of necroptosis [16].”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [16]
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Ferroptosis: Death by Lipid Peroxidation
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TRAF2 is a biologically important necroptosis suppressor
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- Authors
- Zhou, W., & Yuan, J.
- Affiliations
- Harvard University (US)
- Corresponding author
- Yuan, Junying
- Venue
- Seminars in Cell & Developmental Biology
- Publisher
- Elsevier BV
- Published
- 2014-11
- Volume
- 35
- Pages
- 14-23
- ISSN
- 1084-9521 (ISSN-L)
- OpenAlex
- W1974941717
- Cited by
- 414
- References
- 128
- Citations by year
- 2026: 19 · 2025: 18 · 2024: 19 · 2023: 27 · 2022: 30 · 2021: 53 · 2020: 34 · 2019: 45 · 2018: 46 · 2017: 44 · 2016: 41 · 2015: 32 · 2014: 6
- FWCI
- 3.79
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Seminars in Cell and Developmental Biology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institute on Neurological Diseases and Stroke (1R01NS082257)
- National Institute on Aging (R37 AG012859, 1R01AG047231-01)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- necroptosis, regulated necrosis, death receptor ligands, RIP1 kinase, MLKL, ubiquitination, caspase-8, FADD, apoptosis, inflammation, ischemia-reperfusion injury, neurodegeneration, Gaucher disease, atherosclerosis
- MeSH terms
- Humans, Inflammation, Models, Biological, Necrosis, Protein Kinases, Signal Transduction, Caspase 8, Fas-Associated Death Domain Protein, Receptor-Interacting Protein Serine-Threonine Kinases
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