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The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis |
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| Authors: | Jixi Li Thomas McQuade Ansgar B Siemer Johanna Napetschnig Kenta Moriwaki Yu-Shan Hsiao Ermelinda Damko David Moquin Thomas Walz Ann McDermott Francis Ka-Ming Chan Hao Wu |
| Institution: | 1 Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA 2 Department of Pathology, Program in Immunology and Virology, The University of Massachusetts Medical School, Worcester, MA 01655, USA 3 Department of Chemistry, Columbia University, 3000 Broadway, New York, NY 10027, USA 4 Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA 5 Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA |
| Abstract: | 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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