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

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

Research output: Contribution to journalArticlepeer-review

47 Citations (Scopus)

Abstract

The NLRP3 inflammasome plays a central role in antimicrobial defense as well as in the context of sterile inflammatory 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 understanding of how NLRP3 priming contributes to inflammasome activation remains limited. Here, we show that IKKβ, a kinase activated during priming, induces recruitment of NLRP3 to phosphatidylinositol-4-phosphate (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 formation when IKKβ recruited NLRP3 to PI4P. Studying iPSC-derived human macrophages revealed that the IKKβ-mediated NEK7-independent pathway constitutes the predominant NLRP3 priming mechanism in human myeloid cells. Our results suggest that PI4P binding represents a primed state into which NLRP3 is brought by IKKβ activity.

Original languageEnglish
Pages (from-to)2271-2284.e7
JournalImmunity
Volume55
Issue number12
DOIs
Publication statusPublished - 13 Dec 2022
Externally publishedYes

Keywords

  • NEK7
  • NLRP3
  • iPSCs
  • inflammasome
  • innate immunity
  • macrophages
  • monocytes
  • pattern recognition

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