SND1-Tudor Recognition of Methylated S6K2 Regulates Pancreatic Homeostasis

Staphylococcal nuclease and Tudor domain containing 1 (SND1) is a multifunctional protein with four SN domains and a Tudor domain that recognizes symmetric dimethylarginine (SDMA) modifications. Although highly enriched in the pancreas, its role in this tissue remains unclear. Here, we show that loss of SND1 SDMA-reader activity—via knockout or a Y766L point mutation in the Tudor domain—leads to reduced S6 phosphorylation. Mechanistically, SND1 binds SDMA-modified arginines within the C-terminal glycine- and arginine-rich (GAR) motif of S6K2, a kinase also highly expressed in the pancreas. To evaluate the functional relevance of this interaction, we generated S6k2 RK mice carrying lysine substitutions at the GAR arginines, which abolished SND1 recognition. Transcriptomic profiling revealed a strong overlap in dysregulated genes and pathways—including the unfolded protein response and metabolic programs between Snd1 KI and S6k2 RK pancreata. These findings define a methylation-dependent SND1-S6K2 signaling axis as a critical regulator of pancreatic homeostasis. Overall design: S6k2 RK, Snd1 KI, and the WT littermate mice (8-week old, n=3 per group) were euthanized via CO2 inhalation. The pancreas was rapidly collected and snap-frozen in liquid nitrogen. Frozen tissues were ground into a fine powder, and appropriate amounts were transferred into 1.5 mL Eppendorf tubes for submission to Admera Health for standard RNA sequencing.