Identification of the molecular regulation between cell survival and cell death in response to infection induced inflammasome activation.

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The molecular mechanism that defines whether inflammasome activation leads to cell death or survival and activation of immune cells, is unknown. Inflammasomes are protein complexes that function as cellular pathogen sensors. Upon sensing a pathogen, a member of the caspase cysteine protease family, caspase-1 is activated in inflammasomes. Active caspase-1 cleaves gasdermin-D (GSDMD), that subsequently forms pores throughout the plasma membrane leading to a form of cell death named pyroptosis. Paradoxically, the formation of GSDMD pores on the plasma membrane does not always lead to pyroptosis. It has been described that the endosomal sorting complex required for transport (ESCRT) results in membrane repair. It is not known what are the upstream signals which determine whether damaged membranes are repaired or not. It is an important problem, because without understanding this, the beneficial part of inflammasome activation (cytokine maturation) cannot be uncoupled from the detrimental and highly inflammatory pyroptosis. Based on our preliminary data, our hypothesis is that the ESCRT complex is inactivated via protease cleavage by caspase-2, which promotes pyroptosis. This hypothesis is supported by our preliminary work in which bacterial pore forming toxins trigger the pathogen detection response and stimulate inflammasomes. In this system, caspase-2 interacts with and cleaves the ESCRT associated protein ALIX. The rationale for the research is that, understanding this novel regulation of inflammasome driven pyroptosis could lead to new and innovative approaches to the prevention and treatment of a variety of infectious diseases. To test our central hypothesis and accomplish our overall objective, we formulated two specific aims: 1.) Elucidate the mechanism underlying the inflammasome dependent pyroptosis activation via membrane repair inhibition. Based on the preliminary data herein, our working hypothesis is that one or more regulatory components of ESCRT complex are inactivated by caspase-2 cleavage. 2.) Identify the upstream mechanisms that unleash caspase-2 dependent inactivation of membrane repair mechanisms in pyroptosis.