This project presents a very high risk of failure, but the expected outcomes are also really high, as it could lead to the identification of a novel family of microbial protease sensors, namely the gasdermins (GSDMs).
Current research mostly focuses on understanding host factors that control both inflammasome activation and pyroptosis determinants. Here, we propose that, in addition to host factors, non-host-derived ligands (i.e. microbial or environmental molecules) might directly cleave and process GSDMs, leading to pyroptosis regulation. This hypothesis relies on the fact that i/ GSDMD and GSDME cleavage requires aspartyl proteases (i.e. caspase-1,-11 or caspase-8, and caspase-3, respectively) or the serine protease neutrophil elastase and ii/ microbial proteases including, but not restricted to, aspartyl/serine proteases are known virulence factors in various pathogens or opportunists. For example, both fungal C. albicans Sap and viral HIV-1 PR are aspartyl proteases required for efficient infection. In addition, the S. pyogenes cysteine protease SpeB can cleave and promote maturation of pro-IL-1β. Notably, all these microbial proteases were reported to trigger cell death in cells of various origins. In this context, we recently discovered that cell death induced by the HIV-1 PR aspartyl protease relies on GSDMD. Importantly, caspase-1 seems to play only a minor role in HIV-1 PR-triggered GSDMD-dependent pyroptosis. Here we propose that the HIV-1 PR protease might directly cleave and activate host aspartic protease-sensitive GSDMD and/or GSDME, thus promoting caspase-independent pyroptosis.
In this part of the proposal, we address the following questions:
- Does HIV-1 PR (aspartic) protease directly cleave GSDMs; if so, which ones?
- What is the impact of this process on the protective vs. detrimental function of the immune system?
- Are there other microbial proteases and GSDMs mediating such functions?
Principal Investigator: Etienne Meunier
Other personnel: Rémi Planès, Salimata Bagayoko, Pierre-Jean Bordignon, Karin Santoni