Distinct roles of RIP1–RIP3 hetero- and RIP3–RIP3 homo-interaction in mediating necroptosis
Open accessAbstract
Necroptosis is mediated by a signaling complex called necrosome, containing receptor-interacting protein (RIP)1, RIP3, and mixed-lineage kinase domain-like (MLKL). It is known that RIP1 and RIP3 form heterodimeric filamentous scaffold in necrosomes through their RIP homotypic interaction motif (RHIM) domain-mediated oligomerization, but the signaling events based on this scaffold has not been fully addressed. By using inducible dimer systems we found that RIP1-RIP1 interaction is dispensable for necroptosis; RIP1-RIP3 interaction is required for necroptosis signaling, but there is no necroptosis if no additional RIP3 protein is recruited to the RIP1-RIP3 heterodimer, and the interaction with RIP1 promotes the RIP3 to recruit other RIP3; RIP3-RIP3 interaction is required for necroptosis and RIP3-RIP3 dimerization is sufficient to induce necroptosis; and RIP3 dimer-induced necroptosis requires MLKL. We further show that RIP3 oligomer is not more potent than RIP3 dimer in triggering necroptosis, suggesting that RIP3 homo-interaction in the complex, rather than whether RIP3 has formed homo polymer, is important for necroptosis. RIP3 dimerization leads to RIP3 intramolecule autophosphorylation, which is required for the recruitment of MLKL. Interestingly, phosphorylation of one of RIP3 in the dimer is sufficient to induce necroptosis. As RIP1-RIP3 heterodimer itself cannot induce necroptosis, the RIP1-RIP3 heterodimeric amyloid fibril is unlikely to directly propagate necroptosis. We propose that the signaling events after the RIP1-RIP3 amyloid complex assembly are the recruitment of free RIP3 by the RIP3 in the amyloid scaffold followed by autophosphorylation of RIP3 and subsequent recruitment of MLKL by RIP3 to execute necroptosis.
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Activation of RIPK3 downstream of TNFR1 ligation relies on formation of RIPK1-containing and RIPK3-containing amyloid-like signaling complex known as necrosome, wherein first RIPK1 and then RIPK3 undergo trans-phosphorylation or auto-phosphorylation events required for MLKL recruitment and necroptosis activation.
“In particular, the activation of RIPK3 downstream of TNFR1 ligation relies on the formation of a RIPK1-containing and RIPK3-containing amyloid-like signaling complex commonly known as necrosome [436, 470], wherein first RIPK1 and then RIPK3 undergo a series of trans-phosphorylation or auto-phosphorylation events that are required for MLKL recruitment and necroptosis activation [437, 438, 442, 471]”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [471]
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- Authors
- Wu, X.-N., Yang, Z.-H., Wang, X.-K., Zhang, Y., Wan, H., Song, Y., Chen, X., Shao, J., & Han, J.
- Affiliations
- Xiamen University (CN)
- Corresponding author
- Han, J
- Venue
- Cell Death & Differentiation
- Published
- 2014-06-06
- Volume
- 21
- Issue
- 11
- Pages
- 1709-1720
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC4211369
- OpenAlex
- W2057880516
- Cited by
- 299
- References
- 56
- Citations by year
- 2026: 13 · 2025: 19 · 2024: 20 · 2023: 34 · 2022: 22 · 2021: 31 · 2020: 23 · 2019: 24 · 2018: 29 · 2017: 27 · 2016: 30 · 2015: 18 · 2014: 9
- FWCI
- 11.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ariad Pharmaceuticals
- National Natural Science Foundation of China (111 Project, 973 Program, 2014CB541804, 31221065, 31330047, 91029304, B12001)
- Xiamen University
- Higher Education Discipline Innovation Project (B12001)
- National High-tech Research and Development Program (2012AA02A201)
- National Key Research and Development Program of China (2014CB541804, 31221065, 2013CB944903, 91029304)
- 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
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Keywords
- necroptosis, RIPK1, RIPK3, MLKL, necrosome, amyloid fibrils, signaling complex assembly
- MeSH terms
- Animals, Humans, Necrosis, Phosphorylation, Protein Kinases, Apoptosis, Receptor-Interacting Protein Serine-Threonine Kinases, Protein Multimerization
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