The inflammasome provides the first line of defense within host cells against invading pathogens, for example by triggering the release of cytokines into the extracellular milieu to recruit professional immune cells. In order to perform its biological role, the inflammasome components (NLR-family proteins) must assemble into a functional macromolecular machine in response to the presence of conserved elements of pathogens (such as cell wall components) but then disassemble once the threat has been dealt with. Under certain pathological conditions, we propose that the response to pathogen is no longer controlled, such that the inflammasome is constitutively assembled into a functional state, thus behaving as if the cell is under constant attack, leading to uncontrolled inflammation and its sequelae. By employing the structural imaging techniques electron cryo-microscopy and electron tomography, in conjunction with image analysis and reconstruction approaches, supplemented by complementary biophysical and biochemical assays, we will define the structures of key intermediates in the inflammasome assembly pathway, with NLRP1 serving as a prototypical example. These structures will be compared to the inflammasome machinery formed in the background of polymorphic mutations that are linked to autoimmune diseases such as vitiligo and Crohn s diseases.
The inflammasome provides the first line of defense within host cells against invading pathogens, for example by triggering the release of cytokines into the extracellular milieu to recruit professional immune cells. In order to perform its biological role, the inflammasome must assemble into a functional machine in response to the presence of conserved elements of pathogens (such as cell wall components). Here we will determine its spatial organization.
