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

ABSTRACT: 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 inte

SUBMITTER: Geert van Loo 

PROVIDER: S-SCDT-10_1038-S44321-025-00298-0 | biostudies-other |

REPOSITORIES: biostudies-other