IKKO primes inflammasome formation by recruiting NLRP3 to the trans-Golgi 
network

Schmacke, Niklas A.; O'Duill, Fionan; Gaidt, Moritz M.; Szymanska, Inga; Kamper, Julia M.; Schmid-Burgk, Jonathan L.; Mädler, Sophia C.; Mackens-Kiani, Timur; Kozaki, Tatsuya; Chauhan, Dhruv; Nagl, Dennis; Stafford, Che A.; Harz, Hartmann; Froehlich, Adrian L.; Pinci, Francesca; Ginhoux, Florent; Beckmann, Roland; Mann, Matthias; Leonhardt, Heinrich; Hornung, Veit

doi:10.1016/j.immuni.2022.10.021

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IKKO primes inflammasome formation by recruiting NLRP3 to the trans-Golgi network

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Mädler, Sophia C.
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

Mann, Matthias
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Schmacke, N. A., O'Duill, F., Gaidt, M. M., Szymanska, I., Kamper, J. M., Schmid-Burgk, J. L., et al. (2022). IKKO primes inflammasome formation by recruiting NLRP3 to the trans-Golgi network. Immunity, 55(12), 2271-2284. doi:10.1016/j.immuni.2022.10.021.

Cite as: https://hdl.handle.net/21.11116/0000-000C-821F-F

Abstract

The NLRP3 inflammasome plays a central role in antimicrobial defense as well as in the context of sterile in-flammatory conditions. NLRP3 activity is governed by two independent signals: the first signal primes NLRP3, rendering it responsive to the second signal, which then triggers inflammasome formation. Our un-derstanding of how NLRP3 priming contributes to inflammasome activation remains limited. Here, we show that IKK(3, a kinase activated during priming, induces recruitment of NLRP3 to phosphatidylinositol-4-phos-phate (PI4P), a phospholipid enriched on the trans-Golgi network. NEK7, a mitotic spindle kinase that had previously been thought to be indispensable for NLRP3 activation, was redundant for inflammasome forma-tion when IKK(3 recruited NLRP3 to PI4P. Studying iPSC-derived human macrophages revealed that the IKK(3-mediated NEK7-independent pathway constitutes the predominant NLRP3 priming mechanism in hu-man myeloid cells. Our results suggest that PI4P binding represents a primed state into which NLRP3 is brought by IKK(3 activity.