A methylation-dependent reader couples arginine methylation to S6K2 signaling in vivo
- 1Department of Epigenetics & Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- 2Center for Immunotherapy and Precision Immuno-Oncology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Abstract
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.
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BibTeX
@article{wang2026methylationdependent,
title = {{A methylation-dependent reader couples arginine methylation to S6K2 signaling in vivo}},
author = {Yalong Wang and Bin Liu and Rongjie Fu and Wei He and Daniel J. McGrail and Han Xu and Mark T. Bedford},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.aei1547},
url = {https://www.science.org/doi/10.1126/sciadv.aei1547},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - A methylation-dependent reader couples arginine methylation to S6K2 signaling in vivo
AU - Yalong Wang
AU - Bin Liu
AU - Rongjie Fu
AU - Wei He
AU - Daniel J. McGrail
AU - Han Xu
AU - Mark T. Bedford
PY - 2026
DA - 2026/10/23
JO - Science Advances
DO - 10.1126/sciadv.aei1547
UR - https://www.science.org/doi/10.1126/sciadv.aei1547
AB - 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.
SN - 2375-2548
ER -