Rab11FIP2 controls NLRP3 inflammasome activation through Rab11b

Gravastrand, C.; Yurchenko, M.; Kristensen, S.; Skjesol, A.; Chen, C.; Iqbal, Z.; Dahlen, K. R.; Nonstad, U.; Ryan, L.; Espevik, T.; Husebye, H.

doi:10.1101/2025.05.19.654879

bioRxiv · 10.1101/2025.05.19.654879

Rab11FIP2 controls NLRP3 inflammasome activation through Rab11b

Gravastrand, C.·Yurchenko, M.·Kristensen, S.·Skjesol, A.·Chen, C.·Iqbal, Z.·Dahlen, K. R.·Nonstad, U.·Ryan, L.·Espevik, T.·Husebye, H.

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Abstract

Membrane trafficking through the trans-Golgi network has recently been shown to guide activation of the NLRP3 inflammasome. The GTPases Rab11a and Rab11b, and their effector molecule Rab11-FIP2, are regulators of endosome trafficking and retrograde transport. Rab11-FIP2 binds phosphatidylinositol species including PI4P, enriched in the trans-Golgi network and peripheral endosomes following NLRP3 inflammasome activation. We here demonstrate that Rab11-FIP2 and Rab11b, but not Rab11a, control caspase-1 mediated cleavage of pro-IL-1{beta} and GSDMD, and pyroptotic cell death in human macrophages. Rab11-FIP2 also controlled LPS stimulated IKK{beta} activation by TAK1 and IKK{beta} mediated NLRP3 translocation to the trans-Golgi network. Furthermore, we show that NLRP3 bound Rab11-FIP2 via its KMKK motif and that Rab11-FIP2 interacts with NLRP3 via its N-terminal C2-domain. The formation of PI4P positive endosomes and ASC-specks were also controlled by Rab11-FIP2. Collectively our results demonstrate that Rab11-FIP2 and Rab11b control NLRP3 inflammasome activation on early endosomes in human macrophages.

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Gravastrand, C., Yurchenko, M., Kristensen, S., Skjesol, A., Chen, C., Iqbal, Z., Dahlen, K. R., Nonstad, U., Ryan, L., Espevik, T., Husebye, H.. 2025-05-23. Rab11FIP2 controls NLRP3 inflammasome activation through Rab11b. https://doi.org/10.1101/2025.05.19.654879

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