Enhanced inflammasome signaling due to Pyrin mutations underlie auto-inflammation in Familial Mediterranean Fever (FMF). We obtained evidence that also Otulin-related auto-inflammatory syndrome (ORAS) involves enhanced Pyrin signaling. In this project, we will investigate the mechanisms by which Pyrin signaling is regulated by phosphorylation and linear ubiquitination, and how this modulates Pyrin-mediated auto-inflammation in FMF and ORAS mouse models.