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

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.