The first step in the defence against pathogens is the sensing of non-self derived structures by the innate immune system. The Hornung team and their collaboration partners have discovered that IKKβ, an intracellular enzyme activated during non-self sensing, prepares cells for inflammation-inducing cell death: IKKβ recruits the sensor protein NLRP3 to the trans-Golgi network, thereby priming NLRP3 for activation. Once activated, NLRP3 forms a large protein complex termed the inflammasome, which ultimately induces plasma membrane rupture, killing the cell and inducing inflammation. Their work describes a new priming modality of the NLRP3 inflammasome, advancing the understanding of a central mechanism of innate immunity that has been studied for more than 20 years.
Mechanistic overview of the NLRP3 inflammasome priming mechanism discovered by Schmacke et al. Image: Hornung lab
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
Immunity. 2022 Nov 9:S1074-7613(22)00562-3. Online ahead of print. https://doi.org/10.1016/j.immuni.2022.10.021.