Dynamic Arginine Methylation of Tumor Necrosis Factor (TNF) Receptor-associated Factor 6 Regulates Toll-like Receptor Signaling

• DOI: 10.1074/jbc.m115.653543
• Publication Date: 2015-07-29T01:59:59Z
• Authors: Irina Tikhanovich; Sudhakiranmayi Ku...; Antonio Artigues; Maria T. Villar; Kenneth Dorko; Atta Nawabi; Benjamin Roberts; Steven A. Weinman
• Keywords: Male; TNF Receptor-Associated Factor 6; 0301 basic medicine; Jumonji Domain-Containing Histone Demethylases; Protein-Arginine N-Methyltransferases; Blotting, Western; NF-kappa B; Arginine; Ligands; Methylation; Cell Line; Mice, Inbred C57BL; Repressor Proteins; Kinetics; 03 medical and health sciences; Interleukin-1 Receptor-Associated Kinases; Cell Line, Tumor; Animals; Humans; RNA Interference; Cells, Cultured; Signal Transduction

Arginine methylation is a common post-translational modification, but its role in regulating protein function poorly understood. This study demonstrates that, TNF receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase involved innate immune signaling, regulated by reversible arginine range of primary and cultured cells. Under basal conditions, TRAF6 methylated the methyltransferase PRMT1, this inhibits activity, reducing activation toll-like receptor signaling. In response to ligands, demethylated Jumonji domain JMJD6. Demethylation required for maximal NF-κB. Loss JMJD6 leads reduced response, loss PRMT1 pathway with subsequent desensitization ligands. human cells, variations PRMT1/JMJD6 ratio significantly correlate methylation, NF-κB, magnitude LPS. Reversible opposing effects is, therefore, novel mechanism regulation pathways.