Regulation of the Pyrin inflammasome: looking for the endogenous Signal 2 – PYRIN-SIGNAL-2

Pyrin, encoded by MEFV, detects the inhibition of RhoA GTPases by bacterial toxins and mounts an inflammasome complex. Pyrin deregulation plays a key role in two autoinflammatory diseases. We have demonstrated that pyrin dephosphorylation alone is not sufficient to induce inflammasome activation, indicating that an as-yet unknown second mechanism regulates pyrin activation. The main objective of our project is to decipher this second regulatory mechanism. Robust preliminary data from a large chemical screen indicate that certain steroid metabolites act as signal 2 that we aim at characterizing. To this end, we plan 3 synergistic approaches to characterize these newly identified pyrin activators. This project will (i) analyse the structure-function of these hits, (ii) characterize their molecular mechanisms of activation, and (iii) assess their role in human diseases. We expect to shift the pyrin paradigm from a toxin sensor to a homeostasis-altering molecular process (HAMP) sensor.