A methylation-dependent reader couples arginine methylation to S6K2 signaling in vivo

Arginine methylation regulates diverse cellular processes, yet how methyl-arginine reader proteins couple this modification to kinase signaling in vivo remains poorly defined. Here, we identify staphylococcal nuclease and Tudor domain containing 1 (SND1) as a pancreas-enriched effector that links symmetric dimethylarginine (SDMA) recognition to S6 kinase 2 (S6K2) activation. Disruption of SDMA-mediated binding by a point mutation in the SND1 Tudor domain markedly diminishes ribosomal protein S6 (S6) phosphorylation in the pancreas. Mechanistically, SND1 engages SDMA-modified arginines within the carboxyl-terminal glycine-arginine-rich (GAR) motif of S6K2 and promotes S6K2-dependent S6 phosphorylation. Mice harboring lysine substitutions at these GAR arginines (S6k2 RK) phenocopy Snd1 Tudor-mutant (Snd1 knock-in) animals, exhibiting impaired pancreatic S6 phosphorylation. Transcriptomic analyses reveal extensive overlap in dysregulated pathways between Snd1 and S6k2 mutant pancreata, supporting a shared signaling cascade. Together, these findings establish a methylation-dependent reader-kinase axis that links protein arginine methyltransferase 5-catalyzed arginine methylation to tissue-specific control of ribosome signaling and cellular stress adaptation.