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.; Maedler, 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 und Hornung, Veit (2022): IKKO primes inflammasome formation by recruiting NLRP3 to the trans-Golgi network. In: Immunity, Vol. 55, No. 12: pp. 2271-2284

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.

• Item Type: Journal article
• Faculties: Chemistry and Pharmacy > Department of Pharmacy; Biology
• Subjects: 500 Science > 540 Chemistry; 500 Science > 570 Life sciences; biology
• ISSN: 1074-7613
• Language: English
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 414786233