The RNA-binding protein RRP1 brakes macrophage one-carbon metabolism to suppress autoinflammation

Abstract

RNA-binding proteins (RBP) are important for the initiation and resolution of inflammation, so better understanding of RBP-RNA interactions and their crosstalk with metabolism may provide alternate targets to controlling inflammation. Here we establish global RNA-protein interactome purification (GRPIp) to profile the RBP landscape in inflammatory primary macrophages and identify ribosomal RNA processing 1 (RRP1) as a suppressor of inflammatory innate responses. Mechanistically, RRP1 binds nuclear thymidylate synthetase (Tyms) transcript and decreases TYMS expression post-transcriptionally in inflammatory macrophages, consequently suppressing folate metabolism cycle and inhibiting one-carbon metabolism-driven inflammation. Myeloid-specific RRP1-deficient mice develop severe experimental arthritis with increased pro-inflammatory cytokines and immunologic injury. Meanwhile, in patients with rheumatoid arthritis, RRP1 expression in peripheral blood monocytes negatively correlates with TYMS expression and serum IL-1β levels. Our results thus suggest that RRP1 acts as an anti-inflammatory factor through braking one-carbon metabolism post-transcriptionally, thereby implicating potential strategies for controlling autoinflammation.