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<p>Receptor-interacting protein kinase 3 (RIPK3) drives necroptosis by assembling into functional amyloid fibrils. Here we show that lipids modulate RIPK3 amyloidogenesis by stabilizing an aggregation-prone intermediate. While electrostatic repulsion maintains RIPK3 in a soluble state, charge compensation alone is not sufficient for fibril formation and hydrophobic contacts are required to initiate nucleation. Using solution-state NMR, fluorescence-based assays and polymer-encased lipid particles, we demonstrate that negatively charged membranes selectively recruit RIPK3 and restrict its conformational flexibility, accelerating aggregation. These findings reveal a membrane-guided mechanism for RIPK3 assembly and suggest that lipid surfaces, like those implicated in pathological amyloid formation, may modulate functional amyloidogenesis even in the absence of canonical necroptotic stimuli.</p>

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Membrane charge primes the necroptotic kinase RIPK3 for amyloid assembly

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月21日

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  • Fátima C. Escobedo-González,
  • Andrea Gelardo,
  • Alexandra Reimers,
  • Paula Polonio,
  • Miguel Mompeán,
  • Gustavo A. Titaux-Delgado

摘要

Receptor-interacting protein kinase 3 (RIPK3) drives necroptosis by assembling into functional amyloid fibrils. Here we show that lipids modulate RIPK3 amyloidogenesis by stabilizing an aggregation-prone intermediate. While electrostatic repulsion maintains RIPK3 in a soluble state, charge compensation alone is not sufficient for fibril formation and hydrophobic contacts are required to initiate nucleation. Using solution-state NMR, fluorescence-based assays and polymer-encased lipid particles, we demonstrate that negatively charged membranes selectively recruit RIPK3 and restrict its conformational flexibility, accelerating aggregation. These findings reveal a membrane-guided mechanism for RIPK3 assembly and suggest that lipid surfaces, like those implicated in pathological amyloid formation, may modulate functional amyloidogenesis even in the absence of canonical necroptotic stimuli.