The RIP1/RIP3 Necrosome Forms a Functional Amyloid Signaling Complex Required for Programmed Necrosis
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RIP1 and RIP3 kinases are central players in TNF-induced programmed necrosis. Here, we report that the RIP homotypic interaction motifs (RHIMs) of RIP1 and RIP3 mediate the assembly of heterodimeric filamentous structures. The fibrils exhibit classical characteristics of β-amyloids, as shown by Thioflavin T (ThT) and Congo red (CR) binding, circular dichroism, infrared spectroscopy, X-ray diffraction, and solid-state NMR. Structured amyloid cores are mapped in RIP1 and RIP3 that are flanked by regions of mobility. The endogenous RIP1/RIP3 complex isolated from necrotic cells binds ThT, is ultrastable, and has a fibrillar core structure, whereas necrosis is partially inhibited by ThT, CR, and another amyloid dye, HBX. Mutations in the RHIMs of RIP1 and RIP3 that are defective in the interaction compromise cluster formation, kinase activation, and programmed necrosis in vivo. The current study provides insight into the structural changes that occur when RIP kinases are triggered to execute different signaling outcomes and expands the realm of amyloids to complex formation and signaling.
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Upon necroptosis initiation by TNFR1, RIPK3 is activated by RIPK1 (provided CASP8 is inactive) through mechanism involving physical interaction between their RHIM domains and RIPK1 catalytic activity.
“Upon necroptosis initiation by TNFR1, RIPK3 is activated by RIPK1 (provided that CASP8 is inactive, see below) through a mechanism involving the physical interaction between their respective RIP homotypic interaction motif (RHIM) domains and RIPK1 catalytic activity [436–438].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [437]
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 [437]
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Liu, Y., Fan, C., Zhang, Y., Yu, X., Wu, X., Zhang, X., Zhao, Q., Zhang, H., Xie, Q., Li, M., et al. (2017) · Cell Death & Differentiation · doi:10.1038/cdd.2017.78 · Cited by 42 · see citing works
Wang, Z., Feng, J., Yu, J., & Chen, G. (2019) · Journal of Cell Science · doi:10.1242/jcs.227777 · Cited by 35 · see citing works
Cysteine oxidation triggers amyloid fibril formation of the tumor suppressor p16INK4A
Göbl, C., Morris, V. K., van Dam, L., Visscher, M., Polderman, P. E., Hartlmüller, C., de Ruiter, H., Hora, M., Liesinger, L., Birner-Gruenberger, R., et al. (2020) · Redox Biology · doi:10.1016/j.redox.2019.101316 · Cited by 29 · see citing works
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Essential role for the <scp>TRF</scp>2 telomere protein in adult skin homeostasis
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RIP3 antagonizes a TSC2-mediated pro-survival pathway in glioblastoma cell death
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- Authors
- Li, J., McQuade, T., Siemer, A. B., Napetschnig, J., Moriwaki, K., Hsiao, Y.-S., Damko, E., Moquin, D., Walz, T., McDermott, A., Chan, F. K.-M., & Wu, H.
- Affiliations
- Weill Cornell Medicine (US)
- University of Massachusetts Chan Medical School (US)
- Columbia University (US)
- Harvard University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Wu, Hao
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-07
- Volume
- 150
- Issue
- 2
- Pages
- 339-350
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3664196
- OpenAlex
- W1998983498
- Cited by
- 1,222
- References
- 56
- Citations by year
- 2026: 57 · 2025: 99 · 2024: 88 · 2023: 94 · 2022: 114 · 2021: 103 · 2020: 103 · 2019: 88 · 2018: 108 · 2017: 87 · 2016: 83 · 2015: 63 · 2014: 86 · 2013: 44 · 2012: 5
- FWCI
- 25.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 384 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- Cancer Research Institute
- University of Massachusetts
- National Institutes of Health
- Weill Cornell Medical College
- National Institute of Allergy and Infectious Diseases (AI045937, T32 AI07349, R21AI088502, AI083497, AI088502, R01AI083497, T32AI007349, R01AI045937)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 32520, P30DK032520)
- 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
- RIPK1, RIPK3, necroptosis, necrosome, amyloid fibrils, TNF signaling, kinase activation, Congo red binding, thioflavin T binding
- MeSH terms
- Amino Acid Sequence, Amyloid, Humans, Molecular Sequence Data, Necrosis, Signal Transduction, Sequence Alignment, Receptor-Interacting Protein Serine-Threonine Kinases, Protein Interaction Domains and Motifs
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