Positions in immunology available (Inflammasome Biology)

The inflammasome is an intracellular multiprotein complex that senses sterile tissue damage and infectious agents to initiate innate immune responses. Distinct inflammasomes containing specific sensing molecules exist. The NLRP3 inflammasome is unique as it detects a broad range of cellular stress signals but a primary and converging sensing mechanism initiating inflammasome assembly remains ill-defined. We found that NLRP3 binds altered endomembranes because of disruption of inter-organelle contact sites in response to danger signals. However, little is known about this fundamentally new mechanism of pattern recognition linking organelle spatial organization and innate immunity. The organelle-generated signals sensed by NLRP3 and the mechanisms underlying membrane recruitment and activation of the inflammasome remain largely unexplored and thus will be subject of this proposal. The major limit hampering their identification is the difficulty to disentangle the complex cell response to the variety of stimuli leading to NLRP3 activation. We aim to push this limit through an unprecedented combination of approaches ranging from in vitro reconstitution studies with isolated organelles and artificial liposomes and proteo-lipidomics, to cryo-FIB and cryo-ET imaging, molecular modelling, and in vivo testing of the physiological relevance of in vitro findings. This project will lay the foundation for how altered endomembranes serve as danger-associated molecular patterns to trigger innate immune responses.