The RHIM of the Immune Adaptor Protein TRIF Forms Hybrid Amyloids with Other Necroptosis-Associated Proteins

• Published in: Molecules (Basel, Switzerland) Vol. 27; no. 11; p. 3382
• Main Authors: Baker, Max O D G, Shanmugam, Nirukshan, Pham, Chi L L, Ball, Sarah R, Sierecki, Emma, Gambin, Yann, Steain, Megan, Sunde, Margaret
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 24-05-2022; MDPI
• Subjects: Adapters; Adaptor proteins; Amyloid; Amyloidogenesis; Apoptosis; Assemblies; Cell activation; Cell death; Fibrillogenesis; fibrils; Fibroblasts; functional amyloid; Interferon; Kinases; Necroptosis; Phosphorylation; Protein kinase; Proteins; Receptor mechanisms; RHIM; RIPK; Signal transduction; Toll-like receptors; TRIF; Tumor necrosis factor-TNF; β-Interferon; RIPK; RHIM; TRIF; functional amyloid; fibrils; necroptosis
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27113382

TIR-domain-containing adapter-inducing interferon-β (TRIF) is an innate immune protein that serves as an adaptor for multiple cellular signalling outcomes in the context of infection. TRIF is activated via ligation of Toll-like receptors 3 and 4. One outcome of TRIF-directed signalling is the activation of the programmed cell death pathway necroptosis, which is governed by interactions between proteins that contain a RIP Homotypic Interaction Motif (RHIM). TRIF contains a RHIM sequence and can interact with receptor interacting protein kinases 1 (RIPK1) and 3 (RIPK3) to initiate necroptosis. Here, we demonstrate that the RHIM of TRIF is amyloidogenic and supports the formation of homomeric TRIF-containing fibrils. We show that the core tetrad sequence within the RHIM governs the supramolecular organisation of TRIF amyloid assemblies, although the stable amyloid core of TRIF amyloid fibrils comprises a much larger region than the conserved RHIM only. We provide evidence that RHIMs of TRIF, RIPK1 and RIPK3 interact directly to form heteromeric structures and that these TRIF-containing hetero-assemblies display altered and emergent properties that likely underlie necroptosis signalling in response to Toll-like receptor activation.