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<p>Membrane trafficking through the trans-Golgi network has been shown to guide activation of the NLRP3 inflammasome. Rab11 GTPases and their effector Rab11-FIP2 regulate endosomal trafficking and retrograde transport. Here, we demonstrate that Rab11b and Rab11-FIP2 contribute to NLRP3 and pro-IL-1β stabilization during the inflammasome priming phase, which is followed by inflammasome activation. We show Rab11-FIP2 to promote TAK1 phosphorylation and TAK1-mediated activation of IKKβ, a process controlling NLRP3 translocation to the trans-Golgi network. Human NLRP3 and Rab11-FIP2 bind each other via their phosphatidylinositol-4 phosphate (PI4P)-binding domains KMKK and N-terminal C2 domain, respectively. We also provide evidence indicating that Rab11-FIP2 stabilizes NLRP3 on early endosomes, which is important for ASC speck formation. These findings provide insights into the mechanisms controlling stability and intracellular trafficking of NLRP3 in human macrophages.</p>

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GTPase Rab11b and effector Rab11-FIP2 promote NLRP3 stability during inflammasome priming

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月25日

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  • Caroline S Gravastrand,
  • Maria Yurchenko,
  • Stine Kristensen,
  • Astrid Skjesol,
  • Carmen Chen,
  • Sindre Ullmann,
  • Zunaira Iqbal,
  • Karoline Ruud Dahlen,
  • Kashif Rasheed,
  • Unni Nonstad,
  • Liv Ryan,
  • Terje Espevik,
  • Harald Husebye

摘要

Membrane trafficking through the trans-Golgi network has been shown to guide activation of the NLRP3 inflammasome. Rab11 GTPases and their effector Rab11-FIP2 regulate endosomal trafficking and retrograde transport. Here, we demonstrate that Rab11b and Rab11-FIP2 contribute to NLRP3 and pro-IL-1β stabilization during the inflammasome priming phase, which is followed by inflammasome activation. We show Rab11-FIP2 to promote TAK1 phosphorylation and TAK1-mediated activation of IKKβ, a process controlling NLRP3 translocation to the trans-Golgi network. Human NLRP3 and Rab11-FIP2 bind each other via their phosphatidylinositol-4 phosphate (PI4P)-binding domains KMKK and N-terminal C2 domain, respectively. We also provide evidence indicating that Rab11-FIP2 stabilizes NLRP3 on early endosomes, which is important for ASC speck formation. These findings provide insights into the mechanisms controlling stability and intracellular trafficking of NLRP3 in human macrophages.