Pyrin inflammasome-driven erosive arthritis caused by unprenylated RHO GTPase signaling

Geranylgeranyl pyrophosphate, a non-sterol intermediate of the mevalonate pathway, serves as the substrate for protein geranylgeranylation, a process catalyzed by geranylgeranyl transferase I (GGTase-I). Myeloid-specific deletion of Pggt1b, the gene coding for GGTase-I, leads to spontaneous and severe erosive arthritis in mice; however, the underlying mechanisms remained unclear. In this study, we demonstrate that arthritis in mice with myeloid-specific Pggt1b deficiency is driven by unprenylated GTP-bound small RHO family GTPases, which in turn trigger Pyrin (Mefv) inflammasome activation, GSDMD-dependent macrophage pyroptosis, and IL-1β secretion. We show that although Pggt1b deficiency leads to hyperactivation of RAC1, impaired prenylation alters its proper membrane localization and interaction with effectors, rendering it effectively inactive in vivo. Consequently, unprenylated RHO family signaling promotes Pyrin inflammasome assembly through recruitment to the RAC1 effector IQGAP1. Together, these findings identify a novel inflammatory axis in which non-prenylated RHO GTPase activity promotes spontaneous Pyrin inflammasome activation, pyroptosis, and IL-1β release in macrophages, contributing to inflammatory arthritis in mice.