Project description
Signalling cascade of inflammasomes
Inflammasomes are cytosolic multiprotein oligomers that activate the inflammatory cascade and play a pivotal role in host defence. They function as intracellular surveillance systems, recognising the pathogens or indirectly responding to the perturbation of cellular homeostasis. The EU-funded ENGINES project aims to obtain a detailed framework for Nod-like receptor with pyrin domain 1 (NLRP1) and caspase activation and recruitment domain 8 (CARD8) inflammasomes’ functions. The project will employ omics technologies, cell biological, biochemical and structural biology approaches to elucidate the signalling upstream of NLRP1 and CARD8, the mechanism of action and the structure of these sensors. Screening of pathogen panels in combination with novel humanised mouse models will evaluate the relevance of these inflammasomes for antiviral immunity and immune cell homeostasis.
Objective
Inflammasomes play a pivotal role in host defense. They function as intracellular surveillance systems by sensing pathogens or indirectly by responding to the perturbation of cellular homeostasis. While our understanding of inflammasome biology is growing at a rapid pace, we still have an incomplete understanding of how these systems detect pathogenic insults, or how these sensors operate at the molecular level. Just recently, NLRP1 and the closely related CARD8, a functionally distinct subgroup of inflammasome sensors, have been ‘de-orphanized’ for their unique mode of action. More than other sensors of the inflammasome family, NLRP1 and CARD8 display a high level of divergence across different species and NLRP1 ranks among the top genes experiencing positive selection in primates. In our search for a physiological NLRP1 trigger, we have now made the surprising finding that human NLRP1 operates as a direct sensor for dsRNA, a key non-self signature of viral replication.
To obtain a detailed mechanistic framework for NLRP1 and also CARD8 function, I here propose a challenging and pioneering endeavor: employing functional genomics, proteomics and chemogenomics, we will identify signaling networks upstream of NLRP1 and CARD8. Taking cell biological, biochemical and structural biology approaches, the mechanism of action and structure of these sensors will be elucidated. Further, screening a large panel of pathogens, we will characterize their role in response to infection in vitro and implementing novel humanized mouse models for the NLRP1 and the CARD8 inflammasomes, we will assess the relevance of these sensors for antiviral immunity and immune cell homeostasis in vivo. Altogether, this work will not only comprehensively profile the role of these emerging inflammasome pathways, but also uncover fundamental molecular principles of inflammasome biology. Gaining these insights, this work also holds the promise of developing novel, innovative therapeutic strategies.
Fields of science
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomics
- natural sciencesbiological sciencescell biologycell signaling
- medical and health scienceshealth sciencesinfectious diseases
- medical and health sciencesbasic medicinephysiologyhomeostasis
- natural sciencesbiological sciencesmolecular biologystructural biology
Programme(s)
Topic(s)
Funding Scheme
ERC-ADG - Advanced GrantHost institution
80539 MUNCHEN
Germany