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J Biol Chem. 2015 Sep 4;290(36):22236-49. doi: 10.1074/jbc.M115.653543. Epub 2015 Jul 28.

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

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From the Department of Internal Medicine.
Department of Biochemistry and Molecular Biology, and.
Department of Pharmacology and Toxicology, University of Kansas Medical Center, Kansas City, Kansas 66160.
Department of Surgery.
From the Department of Internal Medicine,


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


Jumonji domain-containing protein 6; TNF receptor associated factor (TRAF); arginine methylation; endotoxin; hepatocyte; innate immunity; macrophage; post-translational modification; protein arginine methyltransferase; toll-like receptor (TLR)

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