The RIP1/RIP3 Necrosome Forms a Functional Amyloid Signaling Complex Required for Programmed Necrosis

By Jixi Li, T. McQuade, Ansgar B. Siemer, Johanna Napetschnig, Kenta Moriwaki, Y. Hsiao, Ermelinda Damko, D. Moquin, Thomas Walz, A. McDermott and 2 more. Cell, 2012

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SUMMARY 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.

Subfields: Cancer Research, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/7182f3937722110764b7d525782c3007982cae0b

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Citations in the corpus

Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade. (2017, neutral): “3D structure of Alzheimer’s amyloid-β(1-42) fibrils.”
Toll-like Receptor 3-mediated Necrosis via TRIF, RIP3, and MLKL* (2013, background): “tional modifications during necrosis (4, 5, 29, 50).”
Necroptosis: Mechanisms and Relevance to Disease (2016, neutral): “In this setting, RIPK3 is activated by RIPK1, which results in the assembly of a RIPK1-and RIPK3-containing amyloid-like signaling complex assisted by HSP90 and the cochaperone cell division cycle 37 (CDC37) (35, 36), which has been dubbed necrosome (37).”
Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018 (2018, background): “that are required for MLKL recruitment and necroptosis activation [437, 438, 442, 471].”
MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates. (2014, background): “Within this complex, RIPK1 and RIPK3 bind to each other by homotypic RIP homotypic interaction motif-domain interactions, allowing them to form amyloid-like fibrillar structures (Li et al., 2012).”
Necroptosis: a regulated inflammatory mode of cell death (2018, background): “Phosphorylation of these proteins at their kinase domain promotes RHIM-mediated interactions of both proteins which results in formation of amyloid-like filamentous signaling complex [38, 39] and culminates with necroptosis.”
Regulation of tumour necrosis factor signalling: live or let die (2015, background): “Instead, the interaction of multiple protein complexes of RIPK3 with non-ubiquitylated or de ubiquitylated RIPK1 via their RHIM domains initiates the formation of a cytosolic amyloid signalling protein complex that has been named the necrosome 99,103 .”
A guide to cell death pathways (2023, positive): “During necroptosis, the interaction of activated RIPK1 with RIPK3 is mediated by their respective homotypic RIP homotypic interaction motifs (RHIM), which form a RHIM-mediated amyloid-like structure, to promote the activation of RIPK3 73,74 .”