IKKβ Primes Inflammasome Formation by Recruiting NLRP3 to the Trans-Golgi Network

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2022 Nov 17

PMID 36384135

Authors

Niklas A Schmacke

Fionan ODuill

Moritz M Gaidt

Inga Szymanska

Julia M Kamper

Jonathan L Schmid-Burgk

Sophia C Madler

Timur Mackens-Kiani

Tatsuya Kozaki

Dhruv Chauhan

Dennis Nagl

Che A Stafford

Hartmann Harz

Adrian L Frohlich

Francesca Pinci

Florent Ginhoux

Roland Beckmann

Matthias Mann

Heinrich Leonhardt

Veit Hornung

Affiliations

Soon will be listed here.

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.

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